The expression and prognostic significance of immune checkpoint molecules across clear cell, papillary and chromophobe renal cell carcinoma subtypes.

OBJECTIVE

To compare the expression of immune checkpoint molecules in tumor cells and tumor microenvironment and their role on prognosis among surgically treated non-metastatic clear cell renal cell carcinoma (ccRCC), papillary RCC (papRCC), and chromophobe RCC (chRCC).

METHODS

We retrospectively evaluated patients undergoing curative partial or radical nephrectomy for non-metastatic RCC between 2015 and 2023, who had available formalin-fixed paraffin-embedded tumor tissue and postoperative follow-up. Immunohistochemical staining was performed for PD-L1, PD-1, and CTLA-4. PD-L1 expression was evaluated using tumor proportion score, combined positive score, and immune cell score, whereas PD-1 and CTLA-4 expression were evaluated using immune cell score. Immunopositivity was defined as ≥1%. Primary outcomes were differences in expression among subtypes and recurrence-free survival (RFS). Cancer-specific survival and overall survival were secondary outcomes.

RESULTS

The study included 103 patients: 34 with ccRCC, 30 with papRCC, and 39 with chRCC. PD-L1 immune cell positivity and PD-1 positivity were higher in ccRCC than in papRCC and chRCC. At a median follow-up of 49 months, disease recurrence occurred in 10 (9.7%) patients, cancer specific- and any cause- death in 8 (7.8%), and 14 patients (13.6%), respectively. PD-1 positivity was associated with worse RFS, CSS, and OS in papRCC, and worse RFS and OS in the overall cohort. CTLA-4 positivity was associated with worse OS in papRCC. No immune checkpoint marker was associated with survival outcomes in ccRCC or chRCC. Due to the lower number of events, multivariable analyses could not be performed for assessing independent role of these differences.

CONCLUSION

Immune checkpoint expression varies across RCC subtypes. PD-1 positivity was associated with worse survival in papRCC, however given the small number of events, this finding is hypothesis-generating and requires validation in larger cohorts.