on many tumor antigens are also expressed

on non-tumour cell components, which can then limit treatment
efficacy.

IMMUNE MEDIATED
RESISTANCE

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The immune system is an active component of the disease as it
recognizes cancer cells. However, tumour cells evade the immune system due to
defects in antigen presentation and loss in antigenicity. This leads to
malignancies and is one of the major reasons for patient to become refractory
to treatment. Tumour cells also escape from the immune system by modifying
tumour microenvironment in an immune-suppressive state. Infact, immunotherapy
refers to the harnessing of the patient’s immune surveillance to cure the
cancer. Several of them have shown promising results.However, there are some
reports of resistance to immunotherapy. Intrinsic resistance is shown in patients who fail to evoke
T cell responses and antitumor activity. Generally,patients with immunodeficient
virus infection, who have received transplants, or  elderly people may not have a strong systemic
immune response because of a decrease in their total T-cell pool 64, 65. Moreover, many tumor antigens are also expressed in
healthy cells, which would lower the response of T cells to these antigens 66. In the tumor microenvironment, secretion of TGF-? and
IL-10 could inhibit the function of T cells 67, 68.  microenvironment In the context of anti-angiogenic therapy, tumours may be
rendered refractory to anti-VEGF therapy by a pro-inflammatory
micro-environment that includes multiple cell types such as myeloid cells and
TAMs that secrete factors compensating for VEGF loss to support angiogenesis64. Depletion of MDSC expansion and recruitment that is mediated
predominantly by secretion of G-CSF in anti-VEGF insensitive experimental
models could rescue responsiveness to VEGF depletion, leading to decreased
vessel density and tumour growth. Expression of checkpoint molecules including lymphocyte activation gene
3, T cell membrane protein 3, and B and T lymphocyte attenuator is able to
inhibit the activity of T cells in the tumor immature

 The adoptive
cell transfer (ACT) as the name suggests is the transfer of cells into
patients. The cells may originate from the patient or a different individual.
This is a way to therapeutically harness the anti-tumour effects of adaptive
immunity in patients. The aim of ACT is to boost a patient’s anticancer
immunity by transplanting T cells that recognize tumour-specific antigens,
leading to elimination of cancer cells.68.  It
is a very effective method but responses are not always sustained. Recent work  suggests that inflammation, especially the
presence of TNF (tumour necrosis factor-?) secreted by infiltrating macrophages
resulting from the initial tumour response leads to environmental changes that
induce loss of the targeted tumour antigens. In summary, the immune system can
be implicated in both inherent, as well as acquired resistance to targeted
therapies.

FUTURE PERSPECTIVES AND
STRATEGIES TO OVERCOME THERAPEUTIC RESISTANCE BY MODULATING TUMOUR
MICROENVIRONMENT

The contribution of TME in the cancer therapeutic resistance
has been discussed above . This discussion elaborates  on the different types of cells that  contribute to the induction of therapeutic resistance
through their independent mechanisms .  Intercellular communication within the tumor
and its heterogeneity both result in increased resistance to various
therapeutic approaches. Moreover, tumor cells often utilize secreted molecules
such as exosomes to communicate. Thus, it would be promising to target
intratumoral interactions in anticancer therapies because they contribute
significantly to the therapeutic resistance of tumor cells. It was seen that
?-elemene treatment  inhibits transfer of
multidrug resistance-associated miRNAs and thus block intercellular
communication in the tumor 115. Myeloid cells develop tumor therapeutic resistance through
alteration of the characteristics of tumor cells, ECM remodeling and
angiogenesis as discussed above. Coculture of MTLn3 cancer cells derived from
primary bone marrow-derived macrophages isolated from cathepsin B- or S-deficient
mice gave results of  impaired cancer
cell invasion than coculture with macrophages from wild-type mice 14. When combined with sorafenib (an inhibitor of tyrosine
protein kinases) treatment, TANs depletion suppressed cancer growth and
angiogenesis 28. However, this  is
not all as other pathways of myeloid cells-induced therapeutic resistance should
be investigated.  Tumor microenvironment has been considered to be of
great importance in various therapeutic attempts including one investigating
the use of nanomedicine 124, 125. Other parts of the tumor microenvironment have been
targets of treatment 126. Bevacizumab (Avastin) which is a variant of anti-VEGF
antibody that targets endothelial cells was approved by the United States Food
and Drug Administration as a therapy for metastatic colorectal cancer 

CONCLUSION

Tumor microenvironment has been implicated in tumor growth,
invasion, and metastasis. There has been a great deal of progress in
understanding how myeloid cells and CAFs in TME can affect cancer itself . In
particular, the mechanism by which tumors 
are generally resistant to conventional therapies has been a subject of
interest in the recent days. We summarized some recent reports revealing signal
cascades relevant to tumor therapeutic resistance. In addition to the
contribution of tumor microenvironments in causing therapeutic resistance
described in this review, other features such as interaction of cancer cells
with the ECM should be evaluated. Utilizing appropriate models that reflect
characteristics of the microenvironment would help us treating cancer
effectively. Moreover, it is desirable to develop therapeutic approaches
targeting multiple signal pathways rather than those involved in sustaining
tumor microenvironments. This will ultimately help improve cancer treatment and
save many lives.

 

 

 

 

 

 on non-tumour cell components, which can then limit treatment
efficacy.

IMMUNE MEDIATED
RESISTANCE

The immune system is an active component of the disease as it
recognizes cancer cells. However, tumour cells evade the immune system due to
defects in antigen presentation and loss in antigenicity. This leads to
malignancies and is one of the major reasons for patient to become refractory
to treatment. Tumour cells also escape from the immune system by modifying
tumour microenvironment in an immune-suppressive state. Infact, immunotherapy
refers to the harnessing of the patient’s immune surveillance to cure the
cancer. Several of them have shown promising results.However, there are some
reports of resistance to immunotherapy. Intrinsic resistance is shown in patients who fail to evoke
T cell responses and antitumor activity. Generally,patients with immunodeficient
virus infection, who have received transplants, or  elderly people may not have a strong systemic
immune response because of a decrease in their total T-cell pool 64, 65. Moreover, many tumor antigens are also expressed in
healthy cells, which would lower the response of T cells to these antigens 66. In the tumor microenvironment, secretion of TGF-? and
IL-10 could inhibit the function of T cells 67, 68.  microenvironment In the context of anti-angiogenic therapy, tumours may be
rendered refractory to anti-VEGF therapy by a pro-inflammatory
micro-environment that includes multiple cell types such as myeloid cells and
TAMs that secrete factors compensating for VEGF loss to support angiogenesis64. Depletion of MDSC expansion and recruitment that is mediated
predominantly by secretion of G-CSF in anti-VEGF insensitive experimental
models could rescue responsiveness to VEGF depletion, leading to decreased
vessel density and tumour growth. Expression of checkpoint molecules including lymphocyte activation gene
3, T cell membrane protein 3, and B and T lymphocyte attenuator is able to
inhibit the activity of T cells in the tumor immature

 The adoptive
cell transfer (ACT) as the name suggests is the transfer of cells into
patients. The cells may originate from the patient or a different individual.
This is a way to therapeutically harness the anti-tumour effects of adaptive
immunity in patients. The aim of ACT is to boost a patient’s anticancer
immunity by transplanting T cells that recognize tumour-specific antigens,
leading to elimination of cancer cells.68.  It
is a very effective method but responses are not always sustained. Recent work  suggests that inflammation, especially the
presence of TNF (tumour necrosis factor-?) secreted by infiltrating macrophages
resulting from the initial tumour response leads to environmental changes that
induce loss of the targeted tumour antigens. In summary, the immune system can
be implicated in both inherent, as well as acquired resistance to targeted
therapies.

FUTURE PERSPECTIVES AND
STRATEGIES TO OVERCOME THERAPEUTIC RESISTANCE BY MODULATING TUMOUR
MICROENVIRONMENT

The contribution of TME in the cancer therapeutic resistance
has been discussed above . This discussion elaborates  on the different types of cells that  contribute to the induction of therapeutic resistance
through their independent mechanisms .  Intercellular communication within the tumor
and its heterogeneity both result in increased resistance to various
therapeutic approaches. Moreover, tumor cells often utilize secreted molecules
such as exosomes to communicate. Thus, it would be promising to target
intratumoral interactions in anticancer therapies because they contribute
significantly to the therapeutic resistance of tumor cells. It was seen that
?-elemene treatment  inhibits transfer of
multidrug resistance-associated miRNAs and thus block intercellular
communication in the tumor 115. Myeloid cells develop tumor therapeutic resistance through
alteration of the characteristics of tumor cells, ECM remodeling and
angiogenesis as discussed above. Coculture of MTLn3 cancer cells derived from
primary bone marrow-derived macrophages isolated from cathepsin B- or S-deficient
mice gave results of  impaired cancer
cell invasion than coculture with macrophages from wild-type mice 14. When combined with sorafenib (an inhibitor of tyrosine
protein kinases) treatment, TANs depletion suppressed cancer growth and
angiogenesis 28. However, this  is
not all as other pathways of myeloid cells-induced therapeutic resistance should
be investigated.  Tumor microenvironment has been considered to be of
great importance in various therapeutic attempts including one investigating
the use of nanomedicine 124, 125. Other parts of the tumor microenvironment have been
targets of treatment 126. Bevacizumab (Avastin) which is a variant of anti-VEGF
antibody that targets endothelial cells was approved by the United States Food
and Drug Administration as a therapy for metastatic colorectal cancer 

CONCLUSION

Tumor microenvironment has been implicated in tumor growth,
invasion, and metastasis. There has been a great deal of progress in
understanding how myeloid cells and CAFs in TME can affect cancer itself . In
particular, the mechanism by which tumors 
are generally resistant to conventional therapies has been a subject of
interest in the recent days. We summarized some recent reports revealing signal
cascades relevant to tumor therapeutic resistance. In addition to the
contribution of tumor microenvironments in causing therapeutic resistance
described in this review, other features such as interaction of cancer cells
with the ECM should be evaluated. Utilizing appropriate models that reflect
characteristics of the microenvironment would help us treating cancer
effectively. Moreover, it is desirable to develop therapeutic approaches
targeting multiple signal pathways rather than those involved in sustaining
tumor microenvironments. This will ultimately help improve cancer treatment and
save many lives.

 

 

 

 on non-tumour cell components, which can then limit treatment
efficacy.

IMMUNE MEDIATED
RESISTANCE

The immune system is an active component of the disease as it
recognizes cancer cells. However, tumour cells evade the immune system due to
defects in antigen presentation and loss in antigenicity. This leads to
malignancies and is one of the major reasons for patient to become refractory
to treatment. Tumour cells also escape from the immune system by modifying
tumour microenvironment in an immune-suppressive state. Infact, immunotherapy
refers to the harnessing of the patient’s immune surveillance to cure the
cancer. Several of them have shown promising results.However, there are some
reports of resistance to immunotherapy. Intrinsic resistance is shown in patients who fail to evoke
T cell responses and antitumor activity. Generally,patients with immunodeficient
virus infection, who have received transplants, or  elderly people may not have a strong systemic
immune response because of a decrease in their total T-cell pool 64, 65. Moreover, many tumor antigens are also expressed in
healthy cells, which would lower the response of T cells to these antigens 66. In the tumor microenvironment, secretion of TGF-? and
IL-10 could inhibit the function of T cells 67, 68.  microenvironment In the context of anti-angiogenic therapy, tumours may be
rendered refractory to anti-VEGF therapy by a pro-inflammatory
micro-environment that includes multiple cell types such as myeloid cells and
TAMs that secrete factors compensating for VEGF loss to support angiogenesis64. Depletion of MDSC expansion and recruitment that is mediated
predominantly by secretion of G-CSF in anti-VEGF insensitive experimental
models could rescue responsiveness to VEGF depletion, leading to decreased
vessel density and tumour growth. Expression of checkpoint molecules including lymphocyte activation gene
3, T cell membrane protein 3, and B and T lymphocyte attenuator is able to
inhibit the activity of T cells in the tumor immature

 The adoptive
cell transfer (ACT) as the name suggests is the transfer of cells into
patients. The cells may originate from the patient or a different individual.
This is a way to therapeutically harness the anti-tumour effects of adaptive
immunity in patients. The aim of ACT is to boost a patient’s anticancer
immunity by transplanting T cells that recognize tumour-specific antigens,
leading to elimination of cancer cells.68.  It
is a very effective method but responses are not always sustained. Recent work  suggests that inflammation, especially the
presence of TNF (tumour necrosis factor-?) secreted by infiltrating macrophages
resulting from the initial tumour response leads to environmental changes that
induce loss of the targeted tumour antigens. In summary, the immune system can
be implicated in both inherent, as well as acquired resistance to targeted
therapies.

FUTURE PERSPECTIVES AND
STRATEGIES TO OVERCOME THERAPEUTIC RESISTANCE BY MODULATING TUMOUR
MICROENVIRONMENT

The contribution of TME in the cancer therapeutic resistance
has been discussed above . This discussion elaborates  on the different types of cells that  contribute to the induction of therapeutic resistance
through their independent mechanisms .  Intercellular communication within the tumor
and its heterogeneity both result in increased resistance to various
therapeutic approaches. Moreover, tumor cells often utilize secreted molecules
such as exosomes to communicate. Thus, it would be promising to target
intratumoral interactions in anticancer therapies because they contribute
significantly to the therapeutic resistance of tumor cells. It was seen that
?-elemene treatment  inhibits transfer of
multidrug resistance-associated miRNAs and thus block intercellular
communication in the tumor 115. Myeloid cells develop tumor therapeutic resistance through
alteration of the characteristics of tumor cells, ECM remodeling and
angiogenesis as discussed above. Coculture of MTLn3 cancer cells derived from
primary bone marrow-derived macrophages isolated from cathepsin B- or S-deficient
mice gave results of  impaired cancer
cell invasion than coculture with macrophages from wild-type mice 14. When combined with sorafenib (an inhibitor of tyrosine
protein kinases) treatment, TANs depletion suppressed cancer growth and
angiogenesis 28. However, this  is
not all as other pathways of myeloid cells-induced therapeutic resistance should
be investigated.  Tumor microenvironment has been considered to be of
great importance in various therapeutic attempts including one investigating
the use of nanomedicine 124, 125. Other parts of the tumor microenvironment have been
targets of treatment 126. Bevacizumab (Avastin) which is a variant of anti-VEGF
antibody that targets endothelial cells was approved by the United States Food
and Drug Administration as a therapy for metastatic colorectal cancer 

CONCLUSION

Tumor microenvironment has been implicated in tumor growth,
invasion, and metastasis. There has been a great deal of progress in
understanding how myeloid cells and CAFs in TME can affect cancer itself . In
particular, the mechanism by which tumors 
are generally resistant to conventional therapies has been a subject of
interest in the recent days. We summarized some recent reports revealing signal
cascades relevant to tumor therapeutic resistance. In addition to the
contribution of tumor microenvironments in causing therapeutic resistance
described in this review, other features such as interaction of cancer cells
with the ECM should be evaluated. Utilizing appropriate models that reflect
characteristics of the microenvironment would help us treating cancer
effectively. Moreover, it is desirable to develop therapeutic approaches
targeting multiple signal pathways rather than those involved in sustaining
tumor microenvironments. This will ultimately help improve cancer treatment and
save many lives.

 

 

 

 

 

 on non-tumour cell components, which can then limit treatment
efficacy.

IMMUNE MEDIATED
RESISTANCE

The immune system is an active component of the disease as it
recognizes cancer cells. However, tumour cells evade the immune system due to
defects in antigen presentation and loss in antigenicity. This leads to
malignancies and is one of the major reasons for patient to become refractory
to treatment. Tumour cells also escape from the immune system by modifying
tumour microenvironment in an immune-suppressive state. Infact, immunotherapy
refers to the harnessing of the patient’s immune surveillance to cure the
cancer. Several of them have shown promising results.However, there are some
reports of resistance to immunotherapy. Intrinsic resistance is shown in patients who fail to evoke
T cell responses and antitumor activity. Generally,patients with immunodeficient
virus infection, who have received transplants, or  elderly people may not have a strong systemic
immune response because of a decrease in their total T-cell pool 64, 65. Moreover, many tumor antigens are also expressed in
healthy cells, which would lower the response of T cells to these antigens 66. In the tumor microenvironment, secretion of TGF-? and
IL-10 could inhibit the function of T cells 67, 68.  microenvironment In the context of anti-angiogenic therapy, tumours may be
rendered refractory to anti-VEGF therapy by a pro-inflammatory
micro-environment that includes multiple cell types such as myeloid cells and
TAMs that secrete factors compensating for VEGF loss to support angiogenesis64. Depletion of MDSC expansion and recruitment that is mediated
predominantly by secretion of G-CSF in anti-VEGF insensitive experimental
models could rescue responsiveness to VEGF depletion, leading to decreased
vessel density and tumour growth. Expression of checkpoint molecules including lymphocyte activation gene
3, T cell membrane protein 3, and B and T lymphocyte attenuator is able to
inhibit the activity of T cells in the tumor immature

 The adoptive
cell transfer (ACT) as the name suggests is the transfer of cells into
patients. The cells may originate from the patient or a different individual.
This is a way to therapeutically harness the anti-tumour effects of adaptive
immunity in patients. The aim of ACT is to boost a patient’s anticancer
immunity by transplanting T cells that recognize tumour-specific antigens,
leading to elimination of cancer cells.68.  It
is a very effective method but responses are not always sustained. Recent work  suggests that inflammation, especially the
presence of TNF (tumour necrosis factor-?) secreted by infiltrating macrophages
resulting from the initial tumour response leads to environmental changes that
induce loss of the targeted tumour antigens. In summary, the immune system can
be implicated in both inherent, as well as acquired resistance to targeted
therapies.

FUTURE PERSPECTIVES AND
STRATEGIES TO OVERCOME THERAPEUTIC RESISTANCE BY MODULATING TUMOUR
MICROENVIRONMENT

The contribution of TME in the cancer therapeutic resistance
has been discussed above . This discussion elaborates  on the different types of cells that  contribute to the induction of therapeutic resistance
through their independent mechanisms .  Intercellular communication within the tumor
and its heterogeneity both result in increased resistance to various
therapeutic approaches. Moreover, tumor cells often utilize secreted molecules
such as exosomes to communicate. Thus, it would be promising to target
intratumoral interactions in anticancer therapies because they contribute
significantly to the therapeutic resistance of tumor cells. It was seen that
?-elemene treatment  inhibits transfer of
multidrug resistance-associated miRNAs and thus block intercellular
communication in the tumor 115. Myeloid cells develop tumor therapeutic resistance through
alteration of the characteristics of tumor cells, ECM remodeling and
angiogenesis as discussed above. Coculture of MTLn3 cancer cells derived from
primary bone marrow-derived macrophages isolated from cathepsin B- or S-deficient
mice gave results of  impaired cancer
cell invasion than coculture with macrophages from wild-type mice 14. When combined with sorafenib (an inhibitor of tyrosine
protein kinases) treatment, TANs depletion suppressed cancer growth and
angiogenesis 28. However, this  is
not all as other pathways of myeloid cells-induced therapeutic resistance should
be investigated.  Tumor microenvironment has been considered to be of
great importance in various therapeutic attempts including one investigating
the use of nanomedicine 124, 125. Other parts of the tumor microenvironment have been
targets of treatment 126. Bevacizumab (Avastin) which is a variant of anti-VEGF
antibody that targets endothelial cells was approved by the United States Food
and Drug Administration as a therapy for metastatic colorectal cancer 

CONCLUSION

Tumor microenvironment has been implicated in tumor growth,
invasion, and metastasis. There has been a great deal of progress in
understanding how myeloid cells and CAFs in TME can affect cancer itself . In
particular, the mechanism by which tumors 
are generally resistant to conventional therapies has been a subject of
interest in the recent days. We summarized some recent reports revealing signal
cascades relevant to tumor therapeutic resistance. In addition to the
contribution of tumor microenvironments in causing therapeutic resistance
described in this review, other features such as interaction of cancer cells
with the ECM should be evaluated. Utilizing appropriate models that reflect
characteristics of the microenvironment would help us treating cancer
effectively. Moreover, it is desirable to develop therapeutic approaches
targeting multiple signal pathways rather than those involved in sustaining
tumor microenvironments. This will ultimately help improve cancer treatment and
save many lives.