Detailed bladder cancer immunoprofiling reveals new clues for immunotherapeutic strategies

Nicole Viveiros; Bianca Ct Flores; João Lobo; Cláudia Martins-Lima; Mariana Cantante; Paula Lopes; Cecilia Deantonio; Cintia Palu; Richard Ca Sainson; Rui Henrique; Carmen Jerónimo

doi:10.1002/cti2.1402

Detailed bladder cancer immunoprofiling reveals new clues for immunotherapeutic strategies

Clin Transl Immunology. 2022 Sep 3;11(9):e1402. doi: 10.1002/cti2.1402. eCollection 2022.

Authors

Nicole Viveiros¹, Bianca Ct Flores¹, João Lobo^{1

2

3}, Cláudia Martins-Lima^{1

4}, Mariana Cantante^{1

2}, Paula Lopes^{1

2}, Cecilia Deantonio⁵, Cintia Palu⁵, Richard Ca Sainson⁵, Rui Henrique^{1

2

3}, Carmen Jerónimo^{1

3}

Affiliations

¹ Cancer Biology and Epigenetics Group Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network) Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC) Porto Portugal.
² Department of Pathology Portuguese Oncology Institute of Porto (IPO Porto) Porto Portugal.
³ Department of Pathology and Molecular Immunology School of Medicine and Biomedical Sciences- University of Porto (ICBAS-UP) Porto Portugal.
⁴ Department of Precision Medicine University of Campania "Luigi Vanvitelli" Naples Italy.
⁵ Kymab, a Sanofi Company Cambridge UK.

Abstract

Objectives: Bladder cancer (BlCa) is the tenth most frequent malignancy worldwide and the costliest to treat and monitor. Muscle-invasive BlCa (MIBC) has a dismal prognosis, entailing the need for alternative therapies for the standard radical cystectomy. Checkpoint blockade immunotherapy has been approved for high-grade non-muscle-invasive BlCa (HG NMIBC) and metastatic disease, but its effectiveness in localised MIBC remains under scrutiny. Herein, we sought to characterise and compare the immune infiltrate of HG NMIBC and MIBC samples, including ICOS expression, a targetable immune checkpoint associated with regulatory T cell(T_regs)-mediated immunosuppression.

Methods: Immunohistochemistry for CD83, CD20, CD68, CD163, CD3, CD8, CD4, FoxP3/ICOS and PD-L1 was performed in HG NMIBC and MIBC samples (n = 206), and positive staining was quantified in the peritumoral and/or intratumoral tissue compartments with QuPath imaging software.

Results: CD20⁺ B cells, CD68⁺ and CD163⁺ tumor-associated macrophages were significantly increased in MIBCs and associated with poor prognosis. In turn, higher infiltration of T cells was associated with prolonged survival, with exception of the CD4⁺ helper subset. Intratumoral expression of CD3 and CD8 was independent prognostic factors for increased disease-free survival (DFS) in multivariable analysis. Remarkably, T_regs (FoxP3⁺/FoxP3⁺ICOS⁺) were found differentially distributed between tissue compartments. PD-L1 immunoexpression independently predicted a shorter DFS and associated with higher infiltration of FoxP3⁺ICOS⁺ T_regs.

Conclusions: Immune infiltrates of HG NMIBC and MIBC display significant differences that may help selecting patients for immunotherapies. Considering ICOS immunoexpression results, it might constitute a relevant therapeutic target, eventually in combination with anti-PD-1/PD-L1 therapies, for certain BlCa patient subsets.

Keywords: ICOS; bladder cancer; digital pathology; immune infiltrate; muscle‐invasive; non‐muscle invasive.