Neoepitopes and CD3-positive and CD8-positive cells in polymerase e-mutated and microsatellite-instable endometrial cancers

We read with interest the Brief Report “Association of Polymerase e-Mutated and microsatellite instable endometrial cancers with neoantigen load, number of tumor infiltrating lymphocytes, and expression of PD-1 and PD-L1” by Howitt and colleagues published online in JAMA Oncology on the 9th July. Over the last few years, we have also studied the interesting subgroup of endometrial cancers (ECs) with mutation in the POLE proofreading exonuclease domain and in particular their association with excellent prognosis not mentioned by Howitt et al in their report

POLE proofreading mutation, immune response and prognosis in endometrial cancer

Endometrial cancers (ECs) with POLE proofreading mutations are typified by ultramutation and excellent prognosis. We investigated whether these were related, and found that POLE-mutant ECs display a robust T cell response that corresponds to an enrichment of antigenic tumor neopeptides. Enhanced immunogenicity may explain the favorable outcome of POLE-mutant ECs. </p

POLE proofreading mutation, immune response and prognosis in endometrial cancer

Endometrial cancers (ECs) with POLE proofreading mutations are typified by ultramutation and excellent prognosis. We investigated whether these were related, and found that POLE-mutant ECs display a robust T cell response that corresponds to an enrichment of antigenic tumor neopeptides. Enhanced immunogenicity may explain the favorable outcome of POLE-mutant ECs. </p

Adjuvant treatment for POLE proofreading domain-mutant cancers: sensitivity to radiotherapy, chemotherapy, and nucleoside analogues

Purpose: Pathogenic POLE proofreading domain mutations are found in many malignancies where they are associated with ultramutation and favorable prognosis. The extent to which this prognosis depends on their sensitivity to adjuvant treatment is unknown, as is the optimal therapy for advanced-staged or recurrent POLE-mutant cancers. Experimental design: We examined the recurrence-free survival of women with POLE-mutant and POLE-wild-type endometrial cancers (ECs) in the observation arm of the randomized PORTEC-1 EC trial (N=245 patients with stage I EC for analysis). Sensitivity to radiotherapy and selected chemotherapeutics was compared between Pole-mutant mouse embryonic stem (mES) cells, generated using CRISPR-Cas9 (Pole mutations D275A/E275A, and cancer-associated P286R, S297F, V411L) and isogenic wild-type cell lines. Results: In the observation arm of the PORTEC-1 trial (N=245), women with POLE-mutant ECs (N=16) had an improved recurrence-free survival (10yr RFS 100% vs 80.1% for POLE-wild-type; HR=0.143, 95% CI=0.001-0.996, P=0.049). Pole mutations did not increase sensitivity to radiotherapy nor to chemotherapeutics in mES cells. In contrast, Pole-mutant cells displayed significantly increased sensitivity to cytarabine and fludarabine (IC50 Pole P286R-mutant vs wild-type: 0.05 vs 0.17 μM for cytarabine, 4.62 vs 11.1 μM for fludarabine; P &lt;0.001 for both comparisons). Conclusions: The favorable prognosis of POLE-mutant cancers cannot be explained by increased sensitivity to currently used adjuvant treatments. These results support studies exploring minimization of adjuvant therapy for early-stage POLE-mutant cancers, including endometrial and colorectal cancers. Conversely, POLE mutations result in hypersensitivity to nucleoside analogs, suggesting the use of these compounds as a potentially effective targeted treatment for advanced-stage POLE-mutant cancers

Adjuvant treatment for POLE proofreading domain-mutant cancers: sensitivity to radiotherapy, chemotherapy, and nucleoside analogues

Purpose: Pathogenic POLE proofreading domain mutations are found in many malignancies where they are associated with ultramutation and favorable prognosis. The extent to which this prognosis depends on their sensitivity to adjuvant treatment is unknown, as is the optimal therapy for advanced-staged or recurrent POLE-mutant cancers. Experimental design: We examined the recurrence-free survival of women with POLE-mutant and POLE-wild-type endometrial cancers (ECs) in the observation arm of the randomized PORTEC-1 EC trial (N=245 patients with stage I EC for analysis). Sensitivity to radiotherapy and selected chemotherapeutics was compared between Pole-mutant mouse embryonic stem (mES) cells, generated using CRISPR-Cas9 (Pole mutations D275A/E275A, and cancer-associated P286R, S297F, V411L) and isogenic wild-type cell lines. Results: In the observation arm of the PORTEC-1 trial (N=245), women with POLE-mutant ECs (N=16) had an improved recurrence-free survival (10yr RFS 100% vs 80.1% for POLE-wild-type; HR=0.143, 95% CI=0.001-0.996, P=0.049). Pole mutations did not increase sensitivity to radiotherapy nor to chemotherapeutics in mES cells. In contrast, Pole-mutant cells displayed significantly increased sensitivity to cytarabine and fludarabine (IC50 Pole P286R-mutant vs wild-type: 0.05 vs 0.17 μM for cytarabine, 4.62 vs 11.1 μM for fludarabine; P <0.001 for both comparisons). Conclusions: The favorable prognosis of POLE-mutant cancers cannot be explained by increased sensitivity to currently used adjuvant treatments. These results support studies exploring minimization of adjuvant therapy for early-stage POLE-mutant cancers, including endometrial and colorectal cancers. Conversely, POLE mutations result in hypersensitivity to nucleoside analogs, suggesting the use of these compounds as a potentially effective targeted treatment for advanced-stage POLE-mutant cancers

Naive human T cells can be a source of IL-4 during primary immune responses

IL-4 plays a key role in driving the differentiation of CD4+ Th precursors into Th2 cells, both in mice and in humans. The source of IL-4 during primary immune responses is, however, still debated. When IL-4 consumption in in vitro T cell cultures was blocked with a MoAb to the IL-4 receptor α-chain (IL-4Rα), it became evident that freshly isolated naive (CD45RO−) CD4+ T cells from adults or cord blood produce IL-4 upon activation with anti-CD3 and CD80. IL-4 production by naive T cells is strictly IL-2-dependent. Endogenous IL-4 activity in naive CD4+ T cell cultures modulates the production of interferon-gamma (IFN-γ) on the one hand and IL-5 and IL-13 on the other hand in opposite directions, and it is partly responsible for the low IFN-γ production by cord blood T cells. Comparison of the ratio of IL-4/IFN-γ in supernatants of T cell cultures reveals a skewing towards IL-4 production by cord blood T cells, while naive T cells from (non-atopic) adults predominantly produce IFN-γ. We conclude that CD4+ naive T cells can produce IL-4 without the need for Th2 differentiation, and therefore that they can be the initial source of IL-4 required at the time of priming for T cell differentiation into Th2 cells