B7H3 Immune Checkpoint Overexpression Is Associated with Decreased Complete Response Rates to Neoadjuvant Therapy in Locally Advanced Rectal Cancer

Abstract

Background and objectives: Rectal cancer accounts for approximately one-third of colorectal cancers, with over 340,000 deaths globally in 2022. Despite advancements in treatment, the five-year overall survival for locally advanced rectal cancer (LARC) remains at 74%, with significant morbidity. B7H3 (CD276), an immune checkpoint protein, plays a role in tumor progression and resistance to therapy, and correlates with poor prognosis in various cancers, including colorectal cancer. This study aims to evaluate the expression of B7H3 in LARC and its impact on overall complete response (oCR) rates to neoadjuvant therapy.

Methods: A retrospective study was conducted on 60 patients with LARC who received neoadjuvant chemoradiation (nCRT) followed by total mesorectal excision (TME). B7H3 expression was assessed using immunohistochemistry on surgical specimens. Expression levels were categorized as high or low based on a composite score, and their association with oCR rates was analyzed.

Results: High B7H3 expression was observed in 60% of patients, with 73.5% showing expression in more than 50% of tumor cells. Patients who achieved oCR had significantly lower B7H3 expression compared to those with residual disease (p < 0.001). No nuclear expression of B7H3 was detected. No significant correlation was found between B7H3 expression and other clinicopathological variables, except for a higher likelihood of non-restorative surgery in patients with elevated B7H3 levels (p = 0.049). Mucinous adenocarcinoma had high expression of B7H3.

Conclusions: Elevated B7H3 expression is associated with reduced oCR rates in LARC, highlighting its potential role as a prognostic biomarker. Further studies with larger cohorts are warranted to validate these findings and explore B7H3-targeted therapies as a treatment strategy for LARC.

Keywords: B7H3; complete response; locally advanced rectal cancer; radiotherapy.

Figure 1

Roles of B7H3 in cancer (NK, natural killer T lymphocytes) [14,17,18,22,23,24].

Figure 2

Representative expression patterns for B7H3 expression in rectal tumors. (A) No cytoplasmic/membrane staining on diagnostic biopsy tissue in a patient who achieved a pCR (scale bar 100 um at 200×). (B) Low cytoplasmic/membrane staining in a patient who received upfront surgery (validation cohort; scale bar 50 um at 400×). (C) Moderate cytoplasmic/membrane staining on a surgical specimen, which underwent nCRT (test cohort; scale bar 50 um at 400×). (D) High cytoplasmic/membrane staining on a patient with mucinous adenocarcinoma of the rectum, who underwent upfront surgery (validation cohort; scale bar 50 um at 400×).

Figure 3

B7H3 expression on cytoplasm/membrane and tumor stroma. (A) Percentage of positive stained tumor cells. (B) Distribution of stained area intensity. (C) Distribution of composite score; low expression = composite score <4, high expression = composite score ≥4, composite score = expression level × membranal intensity. (D) Distribution of tumor stroma staining.

Figure 4

B7H3 expression in overall responders, incomplete responders, and validation cohort.

Figure 5

(A) Median composite score is significantly lower in patients with oCR compared to patients with residual disease. (B) Distribution of percentage positive cells according to oCR.