过继性T细胞转移抑制淋巴细胞清除后内源性肿瘤特异性CD8⁺ T细胞的恢复

Adoptive T-cell transfer (ACT), where patients are infused with millions of tumor-specific effector T-cells, has proven to be highly effective in hematologic malignancies and is FDA approved as early as a first-line treatment for refractory disease. Unfortunately, extending the benefits of ACT to solid tumors has been largely hindered with challenges intrinsic to solid tumor microenvironments such as intratumoral heterogeneity, where the ACT target antigen is only expressed in a fraction of the tumor. Engaging the endogenous immune system alongside ACT may be one strategy to circumvent the issue of intratumoral heterogeneity by allowing for a broader, more synergistic T-cell response against the tumor. However, the role of endogenous cells in ACT remains poorly understood, and past clinical and preclinical research suggests that ACT does not engage anti-tumor endogenous responses. In this study, we investigated whether ACT and accompanying lymphodepletion may directly suppress the tumor-specific endogenous T cell response in a Kras/p53(KP)-driven autochthonous mouse model of lung adenocarcinoma expressing defined tumor-specific neoantigens, both ACT-targeted and non-targeted. Lung tumor-bearing mice were lymphodepleted (LD) with a standard dose of 150 mg/kg cyclophosphamide intra-peritoneally with or without transfer of 6 million tumor-specific ACT cells intra-vascularly. Our results demonstrate that LD alone depletes endogenous tumor neoantigen-specific CD8 T cells, but these cells largely recover by 3 weeks post-treatment. In contrast, adoptive cell transfer with LD resulted in sustained depletion of endogenous tumor-specific CD8 cells and these cells had reduced expression of effector markers Ki67 (proliferation) and Granzyme B (cytotoxicity). Adoptive cell transfer without LD did not result in a significantly decreased population of endogenous tumor-specific CD8 cells, however results were confounded by a significantly lower number of adoptively transferred cells infiltrating into the lung. These findings suggest that ACT may be playing a suppressive role against the endogenous tumor-specific T cell response when pre-conditioning mice with cyclophosphamide. Further research studying this suppression with lower doses of LD or homeostatic cytokine supplementation (e.g. IL-7/IL-15) could reveal if the suppression is intrinsic to the adoptively transferred cells or cyclophosphamide. Furthermore, future studies into finding ways to overcome this suppression and activate the endogenous immune system, such as neoantigen-targeted vaccination, could be critical to unlocking the full potential of ACT.