Tissue-Resident Memory-like Lymphocytes Demonstrate Effector Activity in Ovarian Cancer

The success of immune checkpoint blockade (ICB) therapies in many cancer types has been associated with T-cell infiltration. However, despite demonstrating the presence of tumor-infiltrating lymphocytes (TIL) in ovarian cancer, it remains poorly responsive to ICB. To address this issue, Anadon and colleagues sought to define TILs that actively recognize tumor antigens in patients with ovarian cancer using the bidirectional process trogocytosis through which immune and target cells extract membrane proteins from one another. Using the trogocytosis-induced transfer of the EpCAM protein from ovarian cancer cells, EpCAM⁺ TILs were found to also express CD103 and CD69, both of which are phenotypic markers of tissue-resident memory (TRM)-like T cells. This particular cell population demonstrated typical markers of tumor reactivity such as higher effector mediators, reduced stemness markers, and higher clonality as compared to the recirculating TIL population. Furthermore, these TRM-like T cells follow a pattern of differentiation, moving from stem-like TRM-like T cells (TRM_stem), to effector TRM-like cells, to those with a highly proliferative signature, and finally turning into truly exhausted T cells. Conversely, recirculating TILs did not follow this same pattern. Additional analyses revealed that only a small subset of recirculating TILs transition to acquire a TRM_stem reservoir, which then move through this differentiation pattern and exhibit tumor antigen reactivity. Moreover, high ratios of these TRM-like cells, especially those that express low levels of TCF1, are associated with improved overall survival and better outcomes in ovarian cancer. Investigation into the mechanisms behind the maintenance of the TRM_stem reservoir indicated a dependence on the quality of T-cell priming as well as antigen persistence at the tumor beds. Thus, this study reveals that ovarian cancer is an immunogenic disease, but it is dependent on a small percentage (13%) of CD8+ TILs representing only 3% of CD8+ clonotypes.

Anadon CM, Yu X, Hänggi K, Biswas S, Chaurio RA, Martin A, et al. Ovarian cancer immunogenicity is governed by a narrow subset of progenitor tissue-resident memory T cells. Cancer Cell 2022 Apr 12 [Epub ahead of print].

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