Neoadjuvant Chemotherapy of Ovarian Cancer Results in Three Patterns of Tumor-Infiltrating Lymphocyte Response with Distinct Implications for Immunotherapy

Abstract

<b>Purpose:</b> Some forms of chemotherapy can enhance antitumor 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 immunologic changes consistent with this possibility.<b>Experimental Design:</b> 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 (<i>n</i> = 90).<b>Results:</b> 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: (i) TIL^high tumors showed increases in multiple immune markers after chemotherapy; (ii) TIL^low tumors underwent similar increases, achieving patterns indistinguishable from the first group; and (iii) TIL^negative cases generally remained negative. Despite the dramatic increases seen in the first two patterns, post-chemotherapy TIL showed limited prognostic significance.<b>Conclusions:</b> Chemotherapy augments pre-existing TIL responses but fails to relieve major immune-suppressive mechanisms or confer significant prognostic benefit. Our findings provide rationale for multipronged approaches to immunotherapy tailored to the baseline features of the tumor microenvironment. <i>Clin Cancer Res; 23(4); 925-34. ©2016 AACR</i>.