Association between Tumor Mutational Burden, Stromal CD8+ Tumor-Infiltrating Lymphocytes, and Clinical Factors in Cervical Cancers Treated with Radiotherapy

Abstract

Background: Tumor mutational burden (TMB) and stromal CD8-positive tumor-infiltrating lymphocytes (CD8⁺TILs) serve important roles in antitumor immune responses to radiotherapy. This study aimed to elucidate the association between TMB, CD8⁺TILs, and clinical factors in patients with cervical cancer treated with radiotherapy.

Methods: Patients with squamous cell carcinoma of the uterine cervix treated with definitive radiotherapy, and with available somatic mutation data and immunohistochemical staining data from identical tumor tissues, were enrolled retrospectively. The association between TMB and/or CD8⁺TIL density and patient characteristics, mutation profiles, and treatment outcome was analyzed.

Results: The study analyzed 44 patients (median follow-up period, 61 months). There was no significant correlation between TMB and CD8⁺TIL density, or between TMB or CD8⁺TIL density and patient characteristics. TMB-high or CD8⁺TIL density-low status was associated with worse overall survival and distant metastasis-free survival; the predictive value of these factors became greater when used in combination. TMB-high or CD8⁺TIL density-high status was associated with ARID1A mutations.

Conclusions: These data indicate independence of TMB and CD8⁺TIL density and the involvement of ARID1A alterations in antitumor immune responses in patients with cervical cancers treated with radiotherapy, warranting further mechanistic research and prospective validation.

Keywords: ARID1A; CD8+ tumor-infiltrating lymphocyte; cervical cancer; immune response; radiotherapy; tumor mutational burden.

Figure 1

Overview of TMB (a) or pre-RT CD8⁺TIL density (b) in patients with cervical cancer treated with definitive radiotherapy (n = 44). Dashed lines indicate median values: 9.5 mut/Mb and 22.5% for TMB and pre-RT CD8⁺TIL density, respectively.

Figure 2

Correlation between TMB and pre-RT CD8⁺TIL density (a), inter-RT CD8⁺TIL density (b), or changes in CD8⁺TIL density between the two timepoints (c) in patients with cervical cancer treated with definitive radiotherapy (n = 44). p and r values, calculated by Spearman’s rank correlation test, are shown.

Figure 3

Probability of OS, PRFS, and DMFS stratified by TMB (a–c), pre-RT CD8⁺TIL density (d–f), or the two factors in combination (g–i). (a,d,g) OS. (b,e,h) PRFS. (c,f,i) DMSF. The patients were dichotomized with TMB or with pre-RT CD8⁺TIL density using the median: 9.5 mut/Mb and 22.5%, respectively. p values assessed by the log-rank test are shown.

Figure 4

Box and whisker plots showing the association between TMB (a) or pre-RT CD8⁺TIL density (b) and mutation status of genes frequently mutated in the study cohort (i.e., prevalence >20%); wt, wild-type; mt, mutant. p values assessed by the Mann–Whitney U test are shown.