Indoleamine 2,3-dioxygenase in endometrial cancer: a targetable mechanism of immune resistance in mismatch repair-deficient and intact endometrial carcinomas

Abstract

Mismatch repair-deficient endometrial carcinomas are optimal candidates for immunotherapy given their high neoantigen loads, robust lymphoid infiltrates, and frequent PD-L1 expression. However, co-opting the PD-1/PD-L1 pathway is just one mechanism that tumors can utilize to evade host immunity. Another immune modulatory molecule that has been demonstrated in endometrial carcinoma is indoleamine 2,3-dioxygenase (IDO). We herein evaluate IDO expression in 60 endometrial carcinomas and assess results in relation to PD-L1 and mismatch repair status. IDO immunohistochemistry was performed on 60 endometrial carcinomas (20 Lynch syndrome (LS)-associated, 20 MLH1 promoter hypermethylated, and 20 mismatch repair-intact). Eight-five percent of endometrial carcinomas showed IDO tumor staining in >1% of cells. Twenty-five percent were positive in >25% of tumor cells and only 7% exceeded 50% staining. Mismatch repair-deficient cancers were more likely than mismatch repair-intact cancers to be >25% IDO-positive (35% vs. 5% p = 0.024). Differences were amplified when Lynch syndrome-associated cases were evaluated in isolation (50% Lynch syndrome-associated vs. 10% mismatch repair-intact and MLH1-hypermethylated, p = 0.001). Of the four cases showing >50% staining, three were Lynch syndrome-associated and one was MLH1-hypermethylated; no mismatch repair-intact cases had >50% staining. Forty-three percent of IDO-positive tumors were also positive for PD-L1, whereas only two cases showed tumoral PD-L1 in the absence of IDO. In summary, IDO expression is prevalent in endometrial carcinomas and diffuse staining is significantly more common in mismatch repair-deficient cancers, particularly Lynch syndrome-associated cases. Given that the majority of PD-L1 positive cancers also express IDO, synergistic combination therapy with anti-IDO and anti-PD1/PD-L1 may be relevant in this tumor type. Furthermore, anti-IDO therapy may be an option for a small subset of mismatch repair-intact cancers.

Molecular Subtype Not Immune Response Drives Outcomes in Endometrial Carcinoma

“…Similar to PD-L1, IDO-1 expression was significantly higher in TIL high tumors and spanned the 4 molecular subtypes. Prior publications have suggested high prevalence of IDO-1 expression in MMRd tumors, particularly Lynch syndrome-associated endometrial cancer (67,68). Our series confirmed this and revealed even higher expression in the POLE subtype.…”

PD‐L1 and IDO expression in cervical and vulvar invasive and intraepithelial squamous neoplasias: implications for combination immunotherapy

“…Work in malignancy has revealed IDO expression in a variety of solid tumour types, including non‐small‐cell lung carcinoma, colorectal carcinoma, breast carcinoma and a variety of gynaecological malignancies . Furthermore, multiple studies have shown enhanced IDO expression at the tumour–stromal interface and in areas of lymphocytic infiltration, suggesting an adaptive mechanism of immune evasion similar to that described with PD‐L1 . Finally, co‐expression of IDO and PD‐L1 has been illustrated in a variety of other tumour types, underscoring the biological rationale for dual inhibition .…”

“…Furthermore, multiple studies have shown enhanced IDO expression at the tumour–stromal interface and in areas of lymphocytic infiltration, suggesting an adaptive mechanism of immune evasion similar to that described with PD‐L1 . Finally, co‐expression of IDO and PD‐L1 has been illustrated in a variety of other tumour types, underscoring the biological rationale for dual inhibition . However, investigations of IDO and PD‐L1 expression in cervical and vulvar neoplasia have been limited, and clinical trials investigating IDO single‐agent and combination therapies have not accounted for IDO biomarker expression.…”

CD47 Blockade Inhibits Tumor Progression through Promoting Phagocytosis of Tumor Cells by M2 Polarized Macrophages in Endometrial Cancer

“…The tumor microenvironment (TME), which is composed of tumor cells, immune cells, tumor-associated fibroblasts, the vascular network, cytokines, and so on [ 5 ], tends to be polarized to an immunosuppressive state to facilitate the tumor immune evasion [ 6 ]. In endometrial cancer, neoplastic cells can exploit a large variety of immune evasion mechanisms, including alterations in the expression of some molecules that inhibit antitumor immune response, such as programmed cell death 1 ligand 1 (PD-L1) and indoleamine-2,3-dioxygenase (IDO) [ 7 , 8 ]. Accumulating evidence indicates that anti-PD-1/PD-L immune checkpoint therapy may be effective in DNA polymerase epsilon- (POLE-) mutated and microsatellite instability (MSI) EC patients [ 9 – 11 ].…”