Inhibition of Microsomal Prostaglandin E2 Synthase Reduces Collagen Deposition in Melanoma Tumors and May Improve Immunotherapy Efficacy by Reducing T-cell Exhaustion.

The arachidonic acid pathway participates in immunosuppression in various types of cancer. Our previous observation detailed that microsomal prostaglandin E2 synthase 1 (mPGES-1), an enzyme downstream of cyclooxygenase 2 (COX-2), limited antitumor immunity in melanoma; in addition, genetic depletion of mPGES-1 specifically enhanced immune checkpoint blockade therapy. The current study set out to distinguish the roles of mPGES-1 from those of COX-2 in tumor immunity and determine the potential of mPGES-1 inhibitors for reinforcing immunotherapy in melanoma. Genetic deletion of mPGES-1 showed different profiles of prostaglandin metabolites from that of COX-2 deletion. In our syngeneic mouse model, mPGES-1-deficient cells exhibited similar tumorigenicity to that of COX-2-deficient cells, despite a lower ability to suppress PGE2 synthesis by mPGES-1 depletion, indicating the presence of factors other than PGE2 that are likely to regulate tumor immunity. RNA-sequencing analysis revealed that mPGES-1 depletion reduced the expressions of collagen-related genes, which have been found to be associated with immunosuppressive signatures. In our mouse model, collagen was reduced in mPGES-1-deficient tumors, and phenotypic analysis of tumor-infiltrating lymphocytes indicated that mPGES-1-deficient tumors had fewer TIM3+ exhausted CD8+ T cells compared with COX-2-deficient tumors. CAY10678, an mPGES-1 inhibitor, was equivalent to celecoxib, a selective COX-2 inhibitor, in reinforcing anti-PD-1 treatment. Our study indicates that mPGES-1 inhibitors represent a promising adjuvant for immunotherapies in melanoma by reducing collagen deposition and T-cell exhaustion. Significance: Collagen is a predominant component of the extracellular matrix that may influence the tumor immune microenvironment for cancer progression. We present here that mPGES-1 has specific roles in regulating tumor immunity, associated with several collagen-related genes and propose that pharmacologic inhibition of mPGES-1 may hold therapeutic promise for improving immune checkpoint-based therapies.

[A case of HER2-positive advanced gastric cancer with extensive lymph node metastasis treated via chemotherapy with a trastuzumab-containing regimen followed by conversion surgery].

A 62-year-old man presented with type 3 gastric cancer (tub1, HER2 positive) in the cardia, with 10-cm direct invasion into the lower esophagus, and extensive lymph node metastasis (Virchow and paraaortic nodes). Trastuzumab (Her), in the XP regimen (capecitabine and cisplatin [CDDP] plus Her; Xeloda®: 2,000 mg/m² on day 1-14, CDDP: 80 mg/m² on day 1, Her: 8(6) mg/kg on day 1), was administered every 3 weeks and repeated for 6 courses. After administering 6 courses of the XP plus Her regimen, without severe adverse events in the patient, computed tomography (CT) revealed shrinkage of both the main tumor and the metastatic sites, by 51%. Esophagectomy and proximal gastrectomy with 3-field lymphadenectomy and gastric tube reconstruction was performed via right thoracotomy and laparotomy (R0). However, Grade 3 pneumonia occurred postoperatively, and the patient was discharged on day 67 after surgery. After treatment, the tumor was histologically evaluated as Grade 1b gastric cancer, and remnant cancer cells also expressed HER2. The patient was too frail to receive adjuvant chemotherapy, and he died of pneumonia 11 months after surgery, without obvious relapse. Perioperative chemotherapy with a regimen containing Her has a possible role in treating advanced HER2-positive gastric cancer. Multiple invasive conversion surgeries might decrease the feasibility of adjuvant chemotherapy and worsen the prognosis.