Spatial immunoprofiling of the intratumoral and peritumoral tissue of renal cell carcinoma patients

Abstract

While the abundance and phenotype of tumor-infiltrating lymphocytes are linked with clinical survival, their spatial coordination and its clinical significance remain unclear. Here, we investigated the immune profile of intratumoral and peritumoral tissue of clear cell renal cell carcinoma patients (n = 64). We trained a cell classifier to detect lymphocytes from hematoxylin and eosin stained tissue slides. Using unsupervised classification, patients were further classified into immune cold, hot and excluded topographies reflecting lymphocyte abundance and localization. The immune topography distribution was further validated with The Cancer Genome Atlas digital image dataset. We showed association between PBRM1 mutation and immune cold topography, STAG1 mutation and immune hot topography and BAP1 mutation and immune excluded topography. With quantitative multiplex immunohistochemistry we analyzed the expression of 23 lymphocyte markers in intratumoral and peritumoral tissue regions. To study spatial interactions, we developed an algorithm quantifying the proportion of adjacent immune cell pairs and their immunophenotypes. Immune excluded tumors were associated with superior overall survival (HR 0.19, p = 0.02) and less extensive metastasis. Intratumoral T cells were characterized with pronounced expression of immunological activation and exhaustion markers such as granzyme B, PD1, and LAG3. Immune cell interaction occurred most frequently in the intratumoral region and correlated with CD45RO expression. Moreover, high proportion of peritumoral CD45RO+ T cells predicted poor overall survival. In summary, intratumoral and peritumoral tissue regions represent distinct immunospatial profiles and are associated with clinicopathologic characteristics.

Integrative Analysis of Histological Textures and Lymphocyte Infiltration in Renal Cell Carcinoma using Deep Learning

“…5f). We replicated the finding in our previously reported Helsinki dataset of 64 ccRCC patients 34 where instead of a cancer texture and its margin we had annotated the intratumoral and peritumoral regions (R=0.60 p<0.001, Fig. 5f).…”

Histologic-Based Tumor-Associated Immune Cells Status in Clear Cell Renal Cell Carcinoma Correlates with Gene Signatures Related to Cancer Immunity and Clinical Outcomes

“…To the best of our knowledge, histologic-based TAICs status for ccRCC has not been extensively investigated. We first compared the association of the three TAICs status with immunohistochemical and gene expression and oncological outcomes, using three methodologies: the three-tier immunophenotypes inflamed, immune desert, or immune-excluded based on the spatial localization of immune cells [ 14 , 32 ]; the four-tier immunophenotypes referred to the novel concept of hot, excluded, immunosuppressed, and cold phenotypes, including the nature, density, immune functional orientation, and distribution of immune cell parameters [ 14 ]; and our proposed inflammation score focuses only on the degree of TAICs. Although these phenotypes were originally defined based on CD8+ TIL, we categorized these phenotypes by histologically identified TAICs.…”

Immune Checkpoint Inhibitors for Genitourinary Cancers: Treatment Indications, Investigational Approaches and Biomarkers

“…In another study, an 11-marker multiplex IF panel-based prognostic score associated with survival of RCC patients, particularly the density of T cell marker CD3-positive cell populations [159]. Interestingly, spatial immune profiling of nephrectomy samples revealed patients with excluded TME had reduced burden of metastatic disease and improved overall survival versus T cell-inflamed TME [160].…”