Questionable Relevance of γδ T Lymphocytes in Renal Cell Carcinoma

Abstract

Adoptive γδ T cell immunotherapy has moved briskly into clinical trials prompted by several small studies suggesting abundant accumulation of γδ T cells within renal cell carcinoma (RCC). In this study, we re-examined levels of γδ T cells within RCC tumors and correlated levels of these cells with pathologic features and outcome associated with this form of cancer. Tissues from 248 consecutive clear cell RCC tumors obtained from 2000 to 2003 were stained and quantified for total CD3+ and γδ T cells per mm2. Wilcoxon rank sum and Kruskal-Wallis tests were used to evaluate associations between T cell amounts and prognostic factors (age, gender, tumor size, stage, grade, tumor necrosis). Cox models were used to assess associations with RCC-specific death. Median numbers of total CD3+ and γδ T cells were 281/mm2 (interquartile range (IQR): 149–536) and 2.6/mm2 (IQR: 1.3–4.6), respectively. The median percentage of CD3+ T cells that were γδ T cells was 1.0% (IQR: 0.4–1.9). This low percentage of intratumoral γδ T cells was diluted even further with rising CD3+ T cell infiltration. Percentages of γδ T cells were not associated with even one single clinicopathologic feature examined. Median follow-up for this study was 3.1 years (48 patients died of RCC) and Cox analysis failed to demonstrate that γδ T cells (hazard ratio = 1.02, p = 0.25) were predictive of RCC-specific death. γδ T cells are rare and not recruited nor expanded within RCC tumors. Percentages of γδ T cells fail to correlate with any prognostic features of RCC nor specific death. As such, the role of γδ T cells in RCC immunobiology remains questionable.

Low Counts of γδ T Cells in Peritumoral Liver Tissue are Related to More Frequent Recurrence in Patients with Hepatocellular Carcinoma after Curative Resection

“…This result was also in accordance with the low levels of intratumoral γδ T cells in other solid tumors, such as renal cancer (Kowalczyk et al, 1996;Inman et al, 2008). In the tumoral tissues, we found that the number of γδ T cells was positively associated with OS when patients were defined as following subgroups: patients with earlystage (BCLC stage A) HCC, or with single tumor, or with well differentiated tumor, or without thrombi, which indicated that the important antitumor role of γδ T cells in early-stage HCC.…”

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

“…[5][6][7] cd TILs, primarily of the Vc9Vd2 cd T cell type, were reported in renal cell carcinomas, albeit with controversial prognostic values. [7][8][9][10] Nasopharyngeal carcinoma patients carry Vc9Vd2 cd T lymphocytes that are functionally impaired in blood 11 but are able to infiltrate and reduce xenografted nasopharyngeal tumors in mice. 12 Likewise, orthotopic xenografts of breast tumors 13 or bladder carcinomas 14 in mice infused with human TCRVc9Vd2 1 lymphocytes also show strong tumor infiltration by cd TILs and subsequent arrest of tumor growth.…”

Harnessing γδ T cells in anticancer immunotherapy

“…gd TILs isolated in various types of cancer, including colorectal, breast, prostate, ovarian and RCC [17,24,25], recognize and kill both the autologous tumor and a broad range of related tumors, presumably via the recognition of shared stress-related ligands, but do not kill nontransformed cells [17,25]. The infiltration of Vg1 and Vd1 gd T cells into necrotizing melanomas (NMMs) significantly correlates with increased survival [26], whereas intratumoral gd T cell infiltration in RCC tumors does not [27]. These studies suggest that gd T cell infiltration might be beneficial; however, the immunoregulatory properties of gd T cells should not be ignored [28].…”