Spatial immunophenotypes predict response to anti-PD1 treatment and capture distinct paths of T cell evasion in triple negative breast cancer

Dora Hammerl; John W M Martens; Mieke Timmermans; Marcel Smid; Anita M Trapman-Jansen; Renée Foekens; Olga I Isaeva; Leonie Voorwerk; Hayri E Balcioglu; Rebecca Wijers; Iris Nederlof; Roberto Salgado; Hugo Horlings; Marleen Kok; Reno Debets

doi:10.1038/s41467-021-25962-0

Spatial immunophenotypes predict response to anti-PD1 treatment and capture distinct paths of T cell evasion in triple negative breast cancer

Nat Commun. 2021 Sep 27;12(1):5668. doi: 10.1038/s41467-021-25962-0.

Authors

Dora Hammerl¹, John W M Martens¹, Mieke Timmermans¹, Marcel Smid¹, Anita M Trapman-Jansen¹, Renée Foekens¹, Olga I Isaeva^{2

3}, Leonie Voorwerk², Hayri E Balcioglu¹, Rebecca Wijers¹, Iris Nederlof², Roberto Salgado^{4

5}, Hugo Horlings^{2

6}, Marleen Kok^{7

8}, Reno Debets⁹

Affiliations

¹ Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
² Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
³ Department of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
⁴ Department of Pathology, GZA-ZNA Ziekenhuizen, Antwerp, Belgium.
⁵ Division of Research, Peter Mac Callum Cancer Center, Melbourne, Australia.
⁶ Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
⁷ Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. [email protected].
⁸ Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. [email protected].
⁹ Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. [email protected].

Abstract

Only a subgroup of triple-negative breast cancer (TNBC) responds to immune checkpoint inhibitors (ICI). To better understand lack of response to ICI, we analyze 681 TNBCs for spatial immune cell contextures in relation to clinical outcomes and pathways of T cell evasion. Excluded, ignored and inflamed phenotypes can be captured by a gene classifier that predicts prognosis of various cancers as well as anti-PD1 response of metastatic TNBC patients in a phase II trial. The excluded phenotype, which is associated with resistance to anti-PD1, demonstrates deposits of collagen-10, enhanced glycolysis, and activation of TGFβ/VEGF pathways; the ignored phenotype, also associated with resistance to anti-PD1, shows either high density of CD163+ myeloid cells or activation of WNT/PPARγ pathways; whereas the inflamed phenotype, which is associated with response to anti-PD1, revealed necrosis, high density of CLEC9A+ dendritic cells, high TCR clonality independent of neo-antigens, and enhanced expression of T cell co-inhibitory receptors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Antigens, CD / metabolism
Antigens, Differentiation, Myelomonocytic / metabolism
Breast / immunology
Breast / pathology
Breast / surgery
Cohort Studies
Datasets as Topic
Drug Resistance, Neoplasm / immunology*
Female
Humans
Immune Checkpoint Inhibitors / pharmacology*
Immune Checkpoint Inhibitors / therapeutic use
Immunophenotyping
Lymphocytes, Tumor-Infiltrating / immunology
Lymphocytes, Tumor-Infiltrating / metabolism
Mastectomy
Neoadjuvant Therapy / methods
Prognosis
Programmed Cell Death 1 Receptor / antagonists & inhibitors*
RNA-Seq
Receptors, Cell Surface / metabolism
Spatial Analysis
T-Lymphocytes / immunology*
T-Lymphocytes / metabolism
Triple Negative Breast Neoplasms / immunology
Triple Negative Breast Neoplasms / pathology
Triple Negative Breast Neoplasms / therapy*
Tumor Escape
Tumor Microenvironment / drug effects
Tumor Microenvironment / immunology
Wnt Signaling Pathway / immunology

Substances

Antigens, CD
Antigens, Differentiation, Myelomonocytic
CD163 antigen
Immune Checkpoint Inhibitors
PDCD1 protein, human
Programmed Cell Death 1 Receptor
Receptors, Cell Surface