Neoadjuvant Chemotherapy of Ovarian Cancer Results in Three Patterns of Tumor-Infiltrating Lymphocyte Response with Distinct Implications for Immunotherapy.
Purpose: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.Experimental Design: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: (i) TILhightumors showed increases in multiple immune markers after chemotherapy; (ii) TILlowtumors underwent similar increases, achieving patterns indistinguishable from the first group; and (iii) TILnegativecases generally remained negative. Despite the dramatic increases seen in the first two patterns, post-chemotherapy TIL showed limited prognostic significance.Conclusions: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.Clin Cancer Res; 23(4); 925-34. ©2016 AACR.
Deeley Research Centre, British Columbia Cancer Agency, Victoria BC, Canada.|Interdisciplinary Oncology Program, Faculty of Medicine, University of British Columbia, Vancouver BC, Canada.|British Columbia Cancer Research Centre, British Columbia Cancer Agency, Vancouver BC, Canada.
Charlotte S
CS
Lo
Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto General Hospital, Toronto, Canada.
Sanaz
S
Sanii
Deeley Research Centre, British Columbia Cancer Agency, Victoria BC, Canada.
David R
DR
Kroeger
Deeley Research Centre, British Columbia Cancer Agency, Victoria BC, Canada.
Katy
K
Milne
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver BC, Canada.
Aline
A
Talhouk
Department of Statistics, University of British Columbia, Vancouver BC, Canada.
Derek S
DS
Chiu
Département de pathologie et biologie cellulaire, Université de Montréal, Montreal QC, Canada.
Kurosh
K
Rahimi
Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto General Hospital, Toronto, Canada.
Patricia A
PA
Shaw
Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto General Hospital, Toronto, Canada.
Blaise A
BA
Clarke
Deeley Research Centre, British Columbia Cancer Agency, Victoria BC, Canada. bnelson@bccrc.ca.|Department of Biochemistry and Microbiology, University of Victoria, Victoria BC, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver BC, Canada.
Brad H
BH
Nelson
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D001952:Bridged-Ring Compounds / Q000008:administration & dosage; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D007167:Immunotherapy; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D010984:Platinum / Q000008:administration & dosage; D011379:Prognosis; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D043823:Taxoids / Q000008:administration & dosage; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
D015703:Antigens, CD; D001952:Bridged-Ring Compounds; D043823:Taxoids; C080625:taxane; D010984:Platinum