CAR-T在针对血液肿瘤的临床试验中疗效显著，但多个靶向实体瘤的CAR-T在临床中效果不佳。实体肿瘤组织中复杂的肿瘤微环境是抑制CAR-T抗肿瘤能力的重要原因之一。本团队研究发现第二代CAR-T在小鼠体内不仅无法清除肿瘤，反而促进了肿瘤的生长，且肿瘤内部检测到大量小鼠髓系细胞；相反，整合TLR2胞内段的第三代CAR-T则可有效抑制实体瘤增殖。我们还发现CD215+髓系细胞可通过分泌IGF-1促进肿瘤增殖。因此，我们提出假说：CAR-T杀伤肿瘤细胞的过程中分泌的促炎症因子会募集髓系细胞，从而形成肿瘤微环境，一方面会抑制CAR-T细胞的肿瘤杀伤能力，另一方面也会促进肿瘤增殖。CAR-T的杀伤和肿瘤微环境作用之间会形成“博弈”，影响肿瘤生长。本项目拟建立人源化小鼠模型验证这一假说，并探索细胞免疫治疗介导的肿瘤微环境对肿瘤免疫耐受形成的调控作用和机制，为研发可克服肿瘤微环境的CAR-T提供新思路。

Chimeric antigen receptor (CAR)-T cell immunotherapies have shown unprecedented success in treating leukemia and lymphoma but limited clinical efficacy in solid tumors. The immune suppressive microenvironment in solid tumors is one of the most important factors that contribute the failures of clinical trials using CAR-T to treat various cancers, including lung cancer and liver cancer. Previously, we found that tumors in the group that were treated with anti-mesothelin 2nd generation CAR-T cells were larger than that not only in the group that were treated with anti-mesothelin TLR2-incopoterated 3rd generation CAR-T cells but also in the groups that were treated with either unspecific T cells or PBS in A549 metastatic xenograft mouse models. In addition, the percentages of myeloid derived suppressive cells (MDCSs) in the tumors from the 2nd generation CAR-T group were significantly higher than that in the tumors from the 3rd generation group. In contrast, anti-mesothelin TLR2-incopoterated 3rd generation CAR-T cells significantly suppressed the growth of tumors in xenografts. We also show that CD215+ myeloid cells are able to promote the proliferation of tumors by secreting IGF-1 in patient-derived xenografts (PDX). Based on these results, we hypothesize that inflammatory factors secreted by CAR-T cells or tumor cells, and cell debris during killing stimulated and recruited mouse tumor-supportive cells, such as MDSCs that easily access to and accumulate in tumors. Then the tumor-supportive cells promoted the expansion of lung cancer cells and overcame the anti-tumor effects of CAR-T cells. However, the 3rd generation CAR-T cells eliminated tumor cells efficiently enough so that tumors hardly formed and grew in xenografts. In this project, we propose that we will investigate how the immunotherapy-induced inflammatory microenvironment regulates the formation of immune tolerance by comparing the immune suppressive microenvironment in the tumors from the xenografts that are treated with 2nd and 3rd generation CAR-T cells and studying the interactions between the CAR-T cells and inflammatory microenvironment within the tumors. The mechanisms revealed from this study will help us to design better CAR-T cell therapies to conquer solid tumors in the future.