Neoadjuvant chemotherapy of ovarian cancer results in three patterns of tumor-infiltrating lymphocyte response with distinct implications for immunotherapy

abstract:
Neoadjuvant chemotherapy of ovarian cancer results in three patterns of tumor-infiltrating lymphocyte response with distinct implications for immunotherapy | Clinical Cancer Research

Purpose: Some forms of chemotherapy can enhance anti-tumor immunity through immunogenic cell death, resulting in increased T cell activation and tumor infiltration. Such effects could potentially sensitize tumors to immunotherapies, including checkpoint blockade. We investigated whether platinum- and taxane-based chemotherapy for ovarian cancer induces immunological changes consistent with this possibility.

Methods: Matched pre- and post-neoadjuvant chemotherapy tumor samples from 26 high-grade serous carcinoma (HGSC) patients were analyzed by immunohistochemistry (IHC) for a large panel of immune cells and associated factors. The prognostic significance of post-chemotherapy TIL patterns was assessed in an expanded cohort (n=90).


Results: Neoadjuvant chemotherapy was associated with increased densities of CD3+, CD8+, CD8+ TIA-1+, PD-1+ and CD20+ TIL. Other immune subsets and factors were unchanged, including CD79a+ CD138+ plasma cells, CD68+ macrophages, and MHC class I on tumor cells. Immunosuppressive cell types were also unchanged, including FoxP3+ PD-1+ cells (putative regulatory T cells), IDO-1+ cells, and PD-L1+ cells (both macrophages and tumor cells). Hierarchical clustering revealed three response patterns: (1) TILhigh tumors showed increases in multiple immune markers after chemotherapy; (2) TILlow tumors underwent similar increases, achieving patterns indistinguishable from the first group; and (3) TILnegative cases generally remained negative. Despite the dramatic increases seen in the first two patterns, post-chemotherapy TIL showed limited prognostic significance. 

Conclusion: Chemotherapy augments pre-existing TIL responses but fails to relieve major immune suppressive mechanisms or confer significant prognostic benefit. Our findings provide rationale for multi-pronged approaches to immunotherapy tailored to the baseline features of the tumor microenvironment.