THE ROLE OF CERVICAL CANCER IMMUNE PROFILE IN OVERALL OUTCOME

Cervical cancer (CC) is the fourth most common cancer in women. Patients show variable response rates to the standard chemoradiation therapy and high mortality. The patient’s immune status can affect cancer progression and response to therapy, as well as disease recurrence. We determined the immune infiltrate composition of locally advanced CC patients with the goal of identifying immune characteristics associated with a clinical response to therapy. The expression levels of CD68+ tumor-associated macrophages (TAMs) and CD8+, CD4+ and FOXP3 tumor-infiltrating lymphocytes (TILs), as well as the immune checkpoint molecules PD-1, PD-L1 and PD-L2 in the stromal and intra-tumoral regions were analyzed by immunohistochemistry. Fifty samples from patients with squamous cell carcinoma or adenocarcinoma segregated into Responder (R, n=26) and Non-Responder (NR, n=24) groups, according to standard chemoradiation therapy response, were studied. Our findings indicate that both groups showed a heterogeneous immune infiltrate within the tumors lesions. We observed the low or high cell densities for all IHC markers, using the median cell densities as cut-off values. R patients showed an increase in inflammatory level tumor, as indicated by higher percentage of TILs, low PD1 expression and more infiltration of CD4+TILs. In the sum of stromal and intra-tumoral CD4 TILs, we observed a difference in the high density of cells in R vs high in NR. R group also has more CD8 infiltration within the tumor (high vs low number of cells in R and high vs low number of cells in NR), when the CD8+TILs tumor-to-stroma ratio was calculated. This suggests an effective cytotoxic immune response in this group. Whereas NR group showed a high number of CD68+ TAMs, CD8+, FOXP3, PD-L1 + PD-L2+ TILs, as well as higher expression of PD-L1 immunoreactive area, compared to the R group. Additionally, our results demonstrate a positive correlation between CD8 vs FOXP3, and CD8 vs PD-L2+ TILs in R, and a negative correlation between the number of CD68+ TAMs vs CD4+, vs FOXP3+ and vs PD-L1 + TILs in the NR group. These findings indicate that R patients display an intense tumor infiltrating immune profile before treatment and NR patients are individual less efficient in the well-coordinated immune response and show pro-tumoral effects. This immune profile in the tumor microenvironment points to possible future predictors of response to therapy in CC patients. Financial support: Pronon 25000.159953/2014-18