Immunotherapy based on autophagy and TAMs
Clarifying how TAMs in TME support or inhibit tumor progression could
lead to the development of more effective therapies. and there is
abundant evidence that it not only has tumoricidal effects but also
adapts and promotes tumorigenesis and metastasis[82,
83]. In fact, the TME could be simply characterized into cold (non T
cell inflamed) or hot (T cell inflamed), the ability of
immunosuppressive cells, including M2 macrophages, to infiltrate highly
into TME is one of the characteristics of ”cold” TME, also known as
”immune rejection” TME[84, 85]. ”hot” TME are
enriched in CD8 lymphocytes and M1 TAMs and characterized by T cell
infiltration and molecular signatures of immune activation, all of which
contribute to an enhanced response to
immunotherapy[84, 85]. Reprogramming
immunosuppressive TME to an immunostimulatory phenotype can enhance the
sensitivity of tumor responses to immunotherapy. Many current tumor
immunotherapies are based on T cells, B cells, NK cells, etc., and
exploring TAMs-related immunotherapy then becomes a new direction and a
breakthrough in the treatment of cancer. Therefore, targeting TAMs will
be considered as a promising strategy for cancer immunotherapy.
Autophagy appears to be one of the most common processes in cancer
immunotherapy, playing a bidirectional role in immunotherapy. Although
the direct link between autophagy and immunotherapy has not been
explored completely, there is growing evidence that autophagy may have a
differential impact, enhancing or attenuating the efficiency of
immunotherapy, on tumor response to immunotherapy, making autophagy a
key factor and potential target for improving the efficiency of
immunotherapy. On the one hand, autophagy contributes to antitumor
immunity. Enhanced autophagy for cancer cell death triggers autocrine or
paracrine ATP signaling, which may serve as a strong mediator of
pro-inflammatory responses by macrophages in the tumor microenvironment,
thereby enhancing anti-tumor immune responses[86].
The autophagosomes isolated from cancer cells can induce strong T cell
responses, promoting adaptive immune responses against tumor cells and
mediating tumor regression[87]. On the other hand,
autophagy promote immune evasion in tumor cells by major mechanisms
including impaired antigen presentation[88, 89],
inhibition of infiltration of anti-tumor immune cells such as
T-lymphocytes[90, 91] and targeting of
tumor-associated immune regulatory cells to immunogenic cells that
promote tumor rejection[92], leading to antitumor
immunotherapy intrinsic resistance. Several recent studies using
genome-wide CRISPR screens have identified autophagy is a key conserved
mechanism in the tumor microenvironment that protects tumor cells from
T-cell killing and drives immune evasion of cancer cells[93-95]. Notably, since autophagy inhibition
produces different effects on different immune cells, when inhibiting
autophagy to enhance the antitumor immune response, it is important to
determine the effect of autophagy inhibition on the respective immune
cells and the antitumor immune response [96].
Based on the fact that induction or inhibition of autophagy contributes
to the efficacy of immunotherapy, exploring autophagic targets and their
modifiers to control autophagy in the tumor microenvironment is an
emerging strategy to promote cancer immunotherapy.
In fact, autophagy level and TAMs both regulate cytotoxic T cell
activity[97]. Sharma[98] et
al. found that targeted inhibition of palmitoyl protein thioesterase 1
(PPT1), a novel regulator of autophagy in cancer cells, enhances
antitumor immune responses by converting the M2 phenotype of macrophages
to the M1 phenotype while increasing T cell-mediated cytotoxicity in
combination with anti-PD-1 therapy. Autophagy is able to lead to poor
antigen presentation in TAM by downregulating MHC expression on
macrophages, thus limiting the ability of T cells and immunotherapy to
kill tumors[61]. When autophagy is blocked,
polarization of TAMs into M1 macrophages improves immunosuppressive TME
and thus enhances immunotherapy for cancer[33, 36,
51]. In a more intuitive way, direct use of autophagy inhibitors, HCQ
blockade of autophagy converts M2 macrophages to M1 and promotes the
sensitivity of tumor cells to chemotherapeutic agents, killing most of
the tumor cells, and the killed tumor cells release tumor antigens to
promote antitumor immunity. At the same time, CD8+ T cells are recruited
into the TME, subjecting tumor cells to a second strike and inducing
more effective tumor killing[99]. The combination
treatment with HCQ and rapamycin also increases the M1/M2 ratio in the
intracranial glioblastoma tumor model by reprogramming the M2-like TAM
to an M1-like phenotype, decreasing the macrophage polarization of M2,
and enhancing T cell-mediated cytotoxicity to improve anti-PD-1
therapy[36]. It has even been reported that if MEK
inhibitors are used in combination with autophagy inhibitors to activate
TAM to convert to an immunogenic M1-like phenotype via the STING/type I
interferon pathway in tumor cells, this is an attractive therapeutic
approach for PDA immunotherapy development[100].
These studies indicate that a blockade of autophagy can ameliorate
immunosuppressive TME through M1 macrophage polarization, which may
enhance the immunotherapy of cancer. However, it was recently shown that
a Listeria-based HCC vaccine can induce autophagy in TAM via the
TLR2/Myd88/NF-κB pathway, which leads to repolarization of macrophages
from the M2 phenotype to the M1 phenotype and recruitment of increasing
amounts of antitumor cytokines. Moreover, the vaccine induced a robust
antitumor response by reshaping the tumor immune microenvironment
through binding PD-1 blockade[101]. Tan[102] et al. revealed that the natural compound
baicalin, a potential immunotherapeutic candidate for hepatocellular
carcinoma, promoted the activation of TRAF2 degradation-related RelB/p52
pathway through the induction of autophagy, initiating the reprogramming
of TAM to M1 macrophages, thereby exerting an inhibitory effect on
hepatocellular carcinoma cells. In addition, TAM induced autophagy in
HCC cells and attenuated the toxic effects of oxaliplatin. This
autophagy-mediated drug resistance mechanism provides a new therapeutic
strategy[103]. Overall, a large body of evidence
suggests that autophagy and TAMs play a crucial role in the tumor cell
stress response and that targeting autophagy is able to reset TAMs for
immunotherapy of cancer. Targeting autophagy regulation and/or TAMs
therapy may be a viable means and a key breakthrough to increase the
effectiveness of immunotherapy.