TIBs Linked With Poor Outcomes With Anti–PD-1 Therapy Plus Axitinib in Metastatic ccRCC

Renal Cell Carcinoma

The presence of tumor-infiltrating B lymphocytes (TIBs) was predictive of worse outcomes in patients with metastatic clear cell renal cell carcinoma (ccRCC) who were treated with combination therapy consisting of axitinib (Inlyta) and an anti–PD-1 agent, according to data from a retrospective analysis.

Findings published in the Journal of Cancer Research and Clinical Oncology showed that patients with high TIBs experienced a lower overall response rate (ORR) with axitinib-based combination therapy vs those with low TIBs (P = .033).

Additionally, shortened overall survival (OS) was reported for patients with high TIBs vs those with low TIBs (P = .007). Notably, a univariate Cox regression model demonstrated that International Society of Urological Pathologists (ISUP) grade (HR for grade III/IV vs I/II, 3.926; 95% CI, 1.463-10.537; P = .007), TIBs (HR for high vs low, 3.013; 95% CI, 1.298-6.994; P = .01), number of metastatic organs (HR for ≥2 vs 1, 2.328; 95% CI, 1.041-5.204; P = .04), and metastasectomy (HR for no vs yes, 3.678; 95% CI, 1.096-12.341; P = .035) were all significant prognostic factors for OS. A multivariate Cox analysis also showed that TIBs were independently predictive of OS outcomes (HR for high vs low, 2.979; 95% CI, 1.260-7.042; P = .013).

Furthermore, high TIBs were associated with shorter progression-free survival (PFS; P = .008). In the univariate Cox regression model, ISUP grade (HR for grade III/IV vs I/II, 2.470; 95% CI, 1.444-4.227; P = .001), TIBs (HR for high vs low, 2.02; 95% CI, 1.179-3.481; P = .011), International Metastatic RCC Database Consortium (IMDC) risk stratification (HR for intermediate vs favorable, 3.012; 95% CI, 1.209-7.519; HR for poor vs favorable, 1.309; 95% CI, 0.615-2.825; P = .026), and metastatic organ number (HR for ≥2 vs 1, 1.713; 95% CI, 1.016-2.889; P = .043) were all prognostic factors for PFS. Study authors also noted that PD-L1 expression (high vs low) exhibited moderate effects on PFS (HR, 1.777; 95% CI, 0.967-3.266; P = .064). The association between high TIBs and PFS was also demonstrated in the multivariate Cox analysis (HR for high vs low, 2.004; 95% CI, 1.112-3.612; P = .021).

“ccRCC belongs to immune ‘hot’ tumors, which [are] marked by large numbers of immune cells infiltrated in the tumor immune microenvironment. In this study, high TIB infiltration correlated with more CD4-positive [P < .001] and CD8-positive T cells [P < .001]in RCC tumor sites,” wrote lead study author Zhiyuan Lin of the Department of Urology at Zhongshan Hospital, Fudan University, in Shanghai, China, and colleagues. “Unlike most tumors, high infiltration of CD8-positive T cells often predicts poor outcomes in [patients with] RCC, [which] suggests that CD8-positive T cells infiltrated in the RCC microenvironment are mostly functionally exhausted.”

Although past research has characterized the role of tumor-infiltrating lymphocytes in antitumor immune response, data regarding the role of TIBs on the efficacy of immune checkpoint inhibitors in RCC is largely unknown, Lin and colleagues explained.

In this retrospective analysis, investigators identified patients with RCC who were treated with axitinib in combination with pembrolizumab (Keytruda) or tislelizumab-jsgr (Tevimbra) between March 2020 and June 2023 at Zhongshan Hospital of Fudan University. Of the 134 patients identified for potential inclusion, 6 were excluded due to being under 18 years of age or over 80 years of age; 4 were excluded due to other tumors; and 9 patients were excluded due to a diagnosis of non-ccRCC.

Baseline demographic, histological, and clinical data for the 115 patients included in the analysis were imported from medical records, electronic databases, and follow-up information. Immunohistochemistry (IHC) was used to identify specific cells, and immune cell counts were independently determined by 2 urologists, who were blinded to the study’s clinical data. The cutoff between low and high TIBs density was 5.0 cells/mm².

Among all patients, the majority were at least 65 years of age (50.4%); male (60%); had tumor, node, metastasis (TNM) stage III/IV disease (63.5%); had ISUP grade I/II disease (52.2%); had only 1 metastatic organ (64.3%); did not undergo metastasectomy (69.6%); did not receive a prior TKI (60%); and had IMDC intermediate-risk disease (59.1%). The anti–PD-1 therapy used in combination with axitinib was pembrolizumab (38.3%) or tislelizumab (61.7%). Eighty patients had low TIBs, and 35 had high TIBs. Notably, all patients underwent prior tumor resection via radical or cytoreductive nephrectomy.

Additional data showed that TIBs density ranged from 0 cells/mm² to 46 cells/mm². Notably, TIB status was not correlated with gender, age, TNM stage, ISUP grade, or number of metastatic organs.

Furthermore, IHC staining showed that high TIBs were associated with increased infiltration of CD4-positive T cells (P < .001), CD8-positive T cells (P < .001), M2 macrophages (P = .020), and regulatory T cells (P = .004).

An analysis using 22 new samples from patients with metastatic ccRCC with high TIBs showed that PD-1, CTLA-4, and TIM-3 positivity was significantly increased on CD4-positive T cells (PD-1, P = .038; CTLA-4, P = .029; TIM-3, P = .002) and CD8-positive T cells (P = 0.006; P = .026; P < .001). Conversely, no significant differences in LAG-3 or TIGIT expression was observed on CD4-positive T cells (LAG-3, P = .179; TIGIT, P = .142) or CD8-positive T cells (P = .212; P = .367).

“Due to [the] single-center and retrospective design, prospective or external validations are needed in order to strengthen [these findings]. Besides, the related mechanism has not been elaborated in this article and should be expounded in-depth in future study,” the study authors concluded. “Nevertheless, our research is still helpful to understand the impact of TIBs in [patients with] metastatic ccRCC treated with [an] anti–PD-1 antibody plus axitinib.”

Reference

Lin Z, Xiao S, Qi Y, Guo J, Lu L. Tumor infiltrating B lymphocytes (TIBs) associate with poor clinical outcomes, unfavorable therapeutic benefit and immunosuppressive context in metastatic clear cell renal cell carcinoma (mccRCC) patients treated with anti-PD-1 antibody plus Axitinib. J Cancer Res Clin Oncol. 2024;150(5):262. doi:10.1007/s00432-024-05803-5