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.