Differential Spatial Gene and Protein Expression Associated with Recurrence Following Chemoradiation for Localized Anal Squamous Cell Cancer

Abstract

The identification of transcriptomic and protein biomarkers prognosticating recurrence risk after chemoradiation of localized squamous cell carcinoma of the anus (SCCA) has been limited by a lack of available fresh tissue at initial presentation. We analyzed archival FFPE SCCA specimens from pretreatment biopsies prior to chemoradiation for protein and RNA biomarkers from patients with localized SCCA who recurred (N = 23) and who did not recur (N = 25). Tumor cells and the tumor microenvironment (TME) were analyzed separately to identify biomarkers with significantly different expression between the recurrent and non-recurrent groups. Recurrent patients had higher mean protein expression of FoxP3, MAPK-activation markers (BRAF, p38-MAPK) and PI3K/Akt activation (phospho-Akt) within the tumor regions. The TME was characterized by the higher protein expression of immune checkpoint biomarkers such as PD-1, OX40L and LAG3. For patients with recurrent SCCA, the higher mean protein expression of fibronectin was observed in the tumor and TME compartments. No significant differences in RNA expression were observed. The higher baseline expression of immune checkpoint biomarkers, together with markers of MAPK and PI3K/Akt signaling, are associated with recurrence following chemoradiation for patients with localized SCCA. These data provide a rationale towards the application of immune-based therapeutic strategies to improve curative-intent outcomes beyond conventional therapies for patients with SCCA.

Biomarkers of pembrolizumab efficacy in advanced anal squamous cell carcinoma: analysis of a phase II clinical trial and a cohort of long-term responders

“…This finding is consistent with other reports which have described low levels of tumor infiltrating T cells in patients with anal cancer with chemoradiation-refractory and/or advanced disease. [50][51][52] While these data suggest that most patients with advanced anal cancer have low levels of T-cell infiltration, interestingly high levels of T-cell infiltration portends a positive prognosis in localized anal cancer suggesting important biological differences in these two disease subgroups. 50 51 In addition to T-cell infiltration, our study examined other potential predictive biomarkers of pembrolizumab sensitivity in anal cancer.…”

Investigation of the potential effects of estrogen receptor modulators on immune checkpoint molecules

“…Nevertheless, the regulation of the PD-1/PD- 1L axis is a complex process, and the role of individual receptors and signaling factors is not easy to quantify. Overstimulation of the PI3K/Akt or JAK/STAT pathway plays an important role in this mechanism 72 – 76 . Depending on the conditions, used animal models and cells or studied patients, the high PI3K/Akt or JAK/STAT activity can be associated with various signaling molecules such as estrogens, IL-6, or EGF 16 , 71 , 77 .…”

New-generation technologies for spatial tissue analysis, indispensable tools for deciphering intratumor heterogeneity in the development of antibody-drug conjugates and radio-immunoconjugates for cancer treatment

“…A very recent paper from the MD Anderson Cancer Center reported on utilization of the same technology, with a 73 immune-related protein probe panel and spatial transcriptomics, in discovery of recurrence biomarkers of localized squamous cell anal cancer treated by chemoradiation. No differences in mRNA expression between recurring and non-recurring samples were observed, whereas recurring tumors had higher expression of FoxP3, BRAF, p38-MAPK, and phospho-Akt proteins in tumor cells, together with higher expression of PD-1, OX40L, and LAG3 in the TME ( 21 ).…”