肿瘤细胞治疗研究
英文原题：CD103 and CD39 coexpression identifies neoantigen-specific cytotoxic T cells in colorectal cancers with low mutation burden.
CD103 与 CD39 的共表达是低突变负荷、错配修复功能完整结直肠癌中新抗原特异性 CD8⁺ T 细胞的特征。
背景：在多种实体瘤中，CD103和CD39表达可标记肿瘤反应性CD8⁺ T细胞。本研究旨在调查这些标志物能否特异鉴定低突变负荷结直肠癌（CRC）中的新抗原特异性T细胞。实验设计：对11例错配修复功能正常（MMR-proficient）CRC及对应健康组织进行全外显子组和RNA测序，以确定潜在新抗原。同时，从肿瘤组织块培养TIL（肿瘤浸润淋巴细胞），并根据CD103和CD39单独或联合表达，对相应肿瘤消化物中的CD8⁺ T细胞进行流式分选。扩增各亚群后，采用合成肽检测其新抗原定向反应性。通过流式细胞术分析T细胞活化标志物，并采用ELISA检测IFN-γ和颗粒酶B释放，以判断新抗原反应性。此外，采用成像质谱细胞术研究CD103⁺CD39⁺细胞毒性T细胞在肿瘤中的定位。结果：新抗原定向反应性仅在总体TIL群体和CD103⁺CD39⁺（双阳性，DP）CD8⁺ T细胞亚群中发现，在双阴性或单阳性亚群中均未发现。总体TIL中检测到、但DP CD8⁺ T细胞中未检测到的新抗原反应性，可归因于CD4⁺ T细胞。肿瘤组织中直接接触癌细胞的CD8⁺ T细胞富集表达CD103和CD39。结论：CD103和CD39共表达是低突变负荷、MMR功能正常CRC中新抗原特异性CD8⁺ T细胞的特征。在过继T细胞转移或工程化T细胞受体疗法中利用这些亚群，是将免疫疗法获益推广至更多CRC患者的有前景途径。
BACKGROUND: Expression of CD103 and CD39 has been found to pinpoint tumor-reactive CD8 + T cells in a variety of solid cancers. We aimed to investigate whether these markers specifically identify neoantigen-specific T cells in colorectal cancers (CRCs) with low mutation burden. EXPERIMENTAL DESIGN: Whole-exome and RNA sequencing of 11 mismatch repair-proficient (MMR-proficient) CRCs and corresponding healthy tissues were performed to determine the presence of putative neoantigens. In parallel, tumor-infiltrating lymphocytes (TILs) were cultured from the tumor fragments and, in parallel, CD8 + T cells were flow-sorted from their respective tumor digests based on single or combined expression of CD103 and CD39. Each subset was expanded and subsequently interrogated for neoantigen-directed reactivity with synthetic peptides. Neoantigen-directed reactivity was determined by flow cytometric analyses of T cell activation markers and ELISA-based detection of IFN- and granzyme B release. Additionally, imaging mass cytometry was applied to investigate the localization of CD103 + CD39 + cytotoxic T cells in tumors. RESULTS: Neoantigen-directed reactivity was only encountered in bulk TIL populations and CD103 + CD39 + (double positive, DP) CD8 + T cell subsets but never in double-negative or single-positive subsets. Neoantigen-reactivity detected in bulk TIL but not in DP CD8 + T cells could be attributed to CD4 + T cells. CD8 + T cells that were located in direct contact with cancer cells in tumor tissues were enriched for CD103 and CD39 expression. CONCLUSION: Coexpression of CD103 and CD39 is characteristic of neoantigen-specific CD8 + T cells in MMR-proficient CRCs with low mutation burden. The exploitation of these subsets in the context of adoptive T cell transfer or engineered T cell receptor therapies is a promising avenue to extend the benefits of immunotherapy to an increasing number of CRC patients.
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