Neoadjuvant Chemotherapy Modulates the Immune Microenvironment in Metastases of Tubo-Ovarian High-Grade Serous Carcinoma

Abstract

Purpose: The purpose of this study was to assess the effect of neoadjuvant chemotherapy (NACT) on immune activation in stage IIIC/IV tubo-ovarian high-grade serous carcinoma (HGSC), and its relationship to treatment response.Experimental Design: We obtained pre-and posttreatment omental biopsies and blood samples from a total of 54 patients undergoing platinum-based NACT and 6 patients undergoing primary debulking surgery. We measured T-cell density and phenotype, immune activation, and markers of cancer-related inflammation using IHC, flow cytometry, electrochemiluminescence assays, and RNA sequencing and related our findings to the histopathologic treatment response.Results: There was evidence of T-cell activation in omental biopsies after NACT: CD4 þ T cells showed enhanced IFNg production and antitumor Th1 gene signatures were increased. T-cell activation was more pronounced with good response to NACT. The CD8 þ T-cell and CD45RO þ memory cell density in the tumor microenvironment was unchanged after NACT but biopsies showing a good therapeutic response had significantly fewer FoxP3 þ T regulatory (Treg) cells. This finding was supported by a reduction in a Treg cell gene signature in postversus pre-NACT samples that was more pronounced in good responders. Plasma levels of proinflammatory cytokines decreased in all patients after NACT. However, a high proportion of T cells in biopsies expressed immune checkpoint molecules PD-1 and CTLA4, and PD-L1 levels were significantly increased after NACT. Conclusions: NACT may enhance host immune response but this effect is tempered by high/increased levels of PD-1, CTLA4, and PD-L1. Sequential chemoimmunotherapy may improve disease control in advanced HGSC. Clin Cancer Res; 22(12); 3025-36. Ó2016 AACR.

Deconstruction of a Metastatic Tumor Microenvironment Reveals a Common Matrix Response in Human Cancers

“…RNA integrity numbers (RIN) were between 8.1 and 9.9. RNA-Seq was performed by Oxford Gene Technology (Benbroke, UK) to ~42x mean depth on the Illumina HiSeq2500 platform, strand-specific, generating 101bp paired-end reads, as previously described (65). The detailed methods regarding RNA sequencing and bioinformatic analysis are provided in the Supplementary Methods.…”

Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non–Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors

“…Pre-treatment biopsies matched with post-treatment resection specimens provide valuable opportunities for examining modulation of the immune response by chemotherapy and evaluating potential predictors of response to neoadjuvant chemotherapy. Early work suggests that TILs increase following neoadjuvant chemotherapy, both cytotoxic and regulatory T cells [208,209]. Importantly, many TILs post-neoadjuvant chemotherapy express CTLA-4, PD-1 and PD-L1 [208], and tumor cell expression of PD-L1 may also be induced by neoadjuvant chemotherapy.…”

“…Early work suggests that TILs increase following neoadjuvant chemotherapy, both cytotoxic and regulatory T cells [208,209]. Importantly, many TILs post-neoadjuvant chemotherapy express CTLA-4, PD-1 and PD-L1 [208], and tumor cell expression of PD-L1 may also be induced by neoadjuvant chemotherapy. These molecules may be considered markers of T cell exhaustion in the appropriate context, and expression of these markers may support the use of immune checkpoint inhibitors following chemotherapy to reawaken the immune response [208].…”

Evaluation of Inflammatory Cells (Tumor Infiltrating Lymphocytes) in Solid Tumors

“…Několik prací se zabývalo i významem TIL ve vztahu k neoadjuvatní chemoterapii [70,71]. Ukazuje se, že počet TIL se u primárně TIL+ nádorů po neoadjuvantní chemoterapii zvyšuje a kromě toho mohou tyto lymfocyty exprimovat CTLA-4, PD-1 a PD-L1, a mohly by tedy být potenciálně imunoterapeuticky ovlivnitelné [70,72].…”

“…Ukazuje se, že počet TIL se u primárně TIL+ nádorů po neoadjuvantní chemoterapii zvyšuje a kromě toho mohou tyto lymfocyty exprimovat CTLA-4, PD-1 a PD-L1, a mohly by tedy být potenciálně imunoterapeuticky ovlivnitelné [70,72]. Toho by se dalo v budoucnu využít zejména u pokročilých inoperabilních nádorů, kde by mohla chemoterapie "nabudit" imunitní odpověď, což je ovšem možné pouze u nádorů, ve kterých byly primárně TIL přítomné [72].…”