Molecular subtype not immune response drives outcomes in endometrial carcinoma

Purpose: Tumors with high mutation load are thought to engender stronger immune responses which in turn promote prolonged patient survival. To investigate this, we assessed tumor-infiltrating lymphocytes (TIL) and immunosuppressive factors across the four molecular subtypes of endometrial cancer (EC), which have characteristic mutation rates ranging from low to ultra-high. Experimental design: 460 ECs were stratified by ProMisE (Proactive Molecular Risk Classifier in Endometrial cancer) into four molecular subtypes: mismatch repair-deficient (MMRd), POLE mutant (POLE), p53 abnormal (p53abn), and p53 wildtype (p53wt). Immune markers (CD3, CD8, CD79a, CD138, PD-1, PD-L1, FoxP3, IDO-1) were quantified by multiplex immunohistochemistry and tested for associations with ProMisE subtype, survival, and other clinicopathological parameters. Results: Two major TIL patterns were observed. TIL high tumors harbored dense T- and B-lineage infiltrates and multiple immunosuppressive features and were common in molecular subtypes associated with high mutation load (MMRd and POLE); however, equally strong responses were seen in significant numbers of p53abn and p53wt tumors, which have characteristically low mutation loads. TIL low tumors were generally devoid of immunological features and more prevalent in p53abn and p53wt ECs, yet were also seen in MMRd and POLE subtypes. In multivariable models involving ProMisE subtype, T-cell markers, TIL clusters, only ProMisE showed independent prognostic significance. Conclusions: Immune response correlates with EC molecular subtype but does not carry independent prognostic significance. Profound variation in immune response is seen across and within EC molecular subtypes, suggesting that assessment of immune response rather than molecular subtype may better predict response to immunotherapy.

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