The correlation of tumor infiltrating lymphocytes and prognosis in metastatic renal cell cancer

Introduction : Renal Cell Carcinoma (RCC) constitutes 2% of all new cancer cases detected in the world and approximately 90% of malignant tumors of kidney origin. Metastasis presents in 20-30% of RCC patients at the time of diagnosis. Metastatic RCC is resistant to many different treatments (chemotherapy, radiotherapy). Also, metastatic RCC is an immunogenic tumor. Treatment with monoclonal antibodies targeting T cell surface receptors responsible for the regulation of the immune response against tumor antigens such as PD-1 and CTLA-4 (cytotoxic T lymphocyte antigen-4) has been developed. A specific patient group responds to these immunotherapy agents. One of the methods used to determine this response is to examine the relationship between tumor infiltrating lymphocyte (TIL) ratio and clinicopathological features of tumors and patient treatment outcomes. The aim of the study is; to discover the role of CD4, CD8 and CD45 TIL in the etiopathogenesis of the disease, to evaluate its response to treatment (tyrosine kinase inhibitors and PD-1 / PDL-1 inhibitors), to determine its relationship with clinical parameters and to discover its role and importance in showing the prognosis. Method: In this study, 60 patients who applied to Gaziantep University, Department of Internal Diseases, Medical Oncology between 26.10.2004 -09.07.2019 and diagnosed with metastatic RCC were retrospectivly evaluated. New sections were taken from the tissues in with tumor and pathology preparations were made. CD4, CD8 and CD45 antibodies dyes were applied to pathology preparations. The ratio of CD4, CD8 and CD45 positive lymphocytes to of the lymphocytes located around the tumor and infiltrating the tumorin the high magnification area total lymphocytes were determined, respectively. Five different areas with the most positively stained cells at high magnification in each tissue were selected and rates are get from the average of these areas. TIL level was compared with survival and response to treatment. Results: 47 of patients (78.3%) were male and 13 (21.7%) of them were female. Male / Female ratio was 3.6. The median age was 63 (37-81). The most common histological subtype was observed as clear cell RCC with 33 patients (55%). %). Lung metastasis was found in 32 (53.3%) of all the patients, while bone metastasis was found in 21 (35%). . It has been found that patients with metastatic RCC follow-up mean overall survival is (OS) 38.37 months (97.06 months-2.30 months) andmean progression-free survival is (PFS) 19.27 months (93.56 months-2.30 months). It has also been determined that the 12-month overall survival of the patients was 94 ± 0.03%, and the 24-month overall survival was 81 ± 0.05%. The 12-month progression-free survival was 85 ± 0.05%, and the 24-month overall survival were73 ± 0.06%. Patients who received immunotherapy (nivolumab) at any level had better overall survival and progression-free survival compared to patients receiving only tyrosine kinase inhibitor therapy (p=0,009, p=0,012, respectively). Higher PFS was detected in patients who received immunotherapy (nivolumab) in the second line therapy (38.69 months-19.81 months) (p = 0.020). The hazard ratio for relapse was HR 2.27 (95% CI, 1.21-8.41) in patients who only received TKI compared to patients who received immunotherapy. In addition to the literature, in the comparison of 3 different treatments in the TKI groups separately with nivolumab in our study, nivolumab; it was associated with significantly higher PFS than the sunitinib and axitinib groups. (p = 0.002, p = 0.039, respectively). When we analyzed the TIL levels of 47 patients who were followed up in the second line therapy in TKI and immunotherapy group according to their PFS duration, PFS was found to be statistically higher in the Low CD4 group compared to the High CD4 group (44.58 months versus 57.98 months) (p = 0.018). The hazard ratio for recurrence in the high CD4 group was found HR 4.74 (95% CI, 1.30-15.40). In our study, statistically significant difference was found between the Low CD8 and High CD8 groups in terms of OS and PFS (p = 0.001, p=0.003, respectively). When we analyzed the TIL levels of 60 patients followed in the pazopanib and sunitinib arm in the 1st line treatment, PFS was found to be statistically higher in the Low CD8 group compared to the High CD8 arm (p = 0.040). The hazard ratio for recurrence in the high CD8 group was HR 3.27 (95% CI, 1.05-7.01). In our study, while higher CD4 / CD8 ratio in patients with clear cell RCC was associated with higher OS (p = 0.009), no difference was found in terms of PFS (p = 0.893). CD8 / CD45 and CD4 / CD45 analysis of significant difference could not be detected between the OS and PFS. While OS was significantly higher in the high CD4 / CD8 group in patients with RCC who received immunotherapy (p = 0.013), there was no significant difference in OS compared to CD4 / CD8 ratio in RCC patients receiving TKI (p = 0.832). There was no significant difference in PFS between low CD4 / CD8 and high CD4 / CD8 patients with RCC who received both immunotherapy and TKI (p = 0.754, p = 0.605). No significant difference was found with OS and PFS in CD8 / CD45 and CD4 / CD45 analysis, respectively, in patients receiving IT and TKI treatment. Conclusion: In our study, the statistically increased OS and PFS in the patient group treated with immunotherapy (nivolumab) after treatment and first-line TKI shows the importance of the use of nivolumab in metastatic RCC. At second line therapy, used immunotherapy (nivolumab) appears to increase the PFS. In patients who experienced relapse under two separate TKI treatments, an additional benefit of nivolumab administration in the 3rd step could not be demonstrated in PFS compared to giving another TKI. It has been revealed that using CD4 TILs in PFS estimation in patients who progressed under TKI in the 1st step and will be given a 2nd step treatment may be significant, but will not be effective in the choice of treatment. In light of the results of our study, we found that the relationship between CD8 TIL level and PFS is inversely proportional. As a contribution to the literature, it has been determined that the CD4 / CD8 ratio can be used to show OS in patients receiving immunotherapy. Keywords: Overall survival; Targeted treatment; Immunotherapy; Progression-free survival; Tumor infiltrating lymphocytes; Renal cell carcinoma