A Blueprint to Advance Colorectal Cancer Immunotherapies

Le, Dung T.; Hubbard-Lucey, Vanessa M.; Morse, Michael A.; Heery, Christopher R.; Dwyer, Andrea; Marsilje, Thomas H.; Brodsky, Arthur N.; Chan, Emily; Deming, Dustin A.; Díaz, Luis A.; Fridman, Wolf‐Herman; Goldberg, Richard M.; Hamilton, Stanley R.; Housseau, Franck; Jaffee, Elizabeth M.; Kang, Seokyung; Krishnamurthi, Smitha; Lieu, Christopher H.; Messersmith, Wells A.; Sears, Cynthia L.; Segal, Neil H.; Yang, Allison L.; Moss, Rebecca A.; Cha, Edward; O’Donnell-Tormey, Jill; Roach, Nancy; Davis, Anjelica Q.; McAbee, Keavy E.; Worrall, Sharyn; Benson, Al B.

doi:10.1158/2326-6066.cir-17-0375

Cited by 60 publications

(53 citation statements)

References 73 publications

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“…Moreover, immunotherapy is rapidly becoming a novel therapy for many cancers, including CRC [14]. However, some patients had been generally resistant to immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

MIR22HG acts as a tumor suppressor via TGFβ/SMAD signaling and facilitates immunotherapy in colorectal cancer

Shao

Song

et al. 2020

Mol Cancer

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Background: Long noncoding RNAs (lncRNAs) are emerging as critical regulatory elements and play fundamental roles in the biology of various cancers. However, we are still lack of knowledge about their expression patterns and functions in human colorectal cancer (CRC). Methods: Differentially expressed lncRNAs in CRC were identified by bioinformatics screen and the level of MIR22HG in CRC and control tissues were determined by qRT-PCR. Cell viability and migration capacities were examined by MTT and transwell assay. Mouse model was used to examine the function and rational immunotherapy of MIR22HG in vivo. Results:We systematically investigated the expression pattern of lncRNAs and revealed MIR22HG acts as a tumor suppressor in CRC. The expression of MIR22HG was significantly decreased in CRC, which was mainly driven by copy number deletion. Reduced expression of MIR22HG was significantly associated with poor overall survival. Silencing of MIR22HG promoted cell survival, proliferation and tumor metastasis in vitro and in vivo. Mechanistically, MIR22HG exerts its tumor suppressive activity by competitively interacting with SMAD2 and modulating the activity of TGFβ pathway. Decreased MIR22HG promoted the epithelial-mesenchymal transition in CRC. Importantly, we found that MIR22HG expression is significantly correlated with CD8A and overexpression of MIR22HG triggers T cell infiltration, enhancing the clinical benefits of immunotherapy. Conclusion: MIR22HG acts as a tumor suppressor in CRC. Our data provide mechanistic insights into the regulation of MIR22HG in TGFβ pathway and facilitates immunotherapy in cancer.

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“…Moreover, immunotherapy is rapidly becoming a novel therapy for many cancers, including CRC [14]. However, some patients had been generally resistant to immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

MIR22HG acts as a tumor suppressor via TGFβ/SMAD signaling and facilitates immunotherapy in colorectal cancer

Shao

Song

et al. 2020

Mol Cancer

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“…Blockade of PD-1/PD-L1 signaling targets exhausted CD8 + T cells. It is effective in highly mutated MSI CRCs, in which the T cell response has already been elicited (67,68). To date, all immune interventions, including PD-1/PD-L1 checkpoint blockade, adoptive T cell transfer, and vaccination, have failed in human MSS CRCs.…”

Section: Discussionmentioning

confidence: 99%

Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice

Ragusa

Prat-Luri

González-Loyola

et al. 2020

Journal of Clinical Investigation

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“…Keeping in mind first, that MSI+ patients are over-represented in the group of tumors with high densities of CD8 T-cells; and second, that patients with High T-cell infiltration have a higher expression of PD-1 and PDL1, and are more likely to respond to ICI; these observations suggest that the response to ICI is strongly dependent on the presence of an established in situ adaptive immune reaction (36,37). We thus questioned, as suggested by Le & al. whether taking into account the evaluation of the in situ immune reaction in the primary tumor together with MSI status could clarify and extend the range of patients eligible to ICI (38). Data of 1579 UICC-TNM stage I/II/III patients with available MSI status were extracted from the Immunoscore international validation study out of which 318 patients (20%) experienced a relapse (31,39).…”

Section: Immunoscore As a New Component Of A Tnm-immune Classificatiomentioning

confidence: 99%

The Immunoscore in the Clinical Practice of Patients with Colon and Rectal Cancers

Zeitoun¹,

Sissy²,

Kirilovsky³

et al. 2019

chr

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RezumatÎn echilibrul perfect dintre invazia tumorală şi sistemele noastre de apărare, rolul jucat de răspunsul imun adaptiv la nivel tumoral este critic. Dincolo de faptul că toate elementele sistemului imun ce intervin în răspunsul imun înnăscut şi cel adaptativ pot fi observate la diferite grade în micromediul tumoral, se pare că există o densitate crescută de limfocite cu memorie T citotoxice, în contextul unei orientări imune Th1 la nivel intratumoral şi al frontului de invazie tumorală, ce oferă un marker de prognostic de importanţă majoră în cancerul colorectal şi în tumorile solide în general. Înţelegerea rolului pe care imunitatea îl are în cancer, în urma unui secol de intensă cercetare, a condus la o schimbare completă a paradigmei. Pentru a arăta impactul major al acestui concept revoluţionar, vom evidenţia aici prin exemplul cancerului colorectal, cum un test imun eficient şi anume "Immunoscore" a fost dezvoltat. De asemenea, oferim date actualizate care demonstrează capacitatea Immunoscorului de a prezice cu o acurateţe superioară stadializării TNM evoluţia clinică a pacienţilor şi ghidarea strategiilor terapeutice. AbstractIn the fine balance between tumor invasion and our defensive systems, the role played by the adaptive immune response at the tumor site is critical. Beyond the fact that all the immune components of the innate and adaptive response can be observed to varying degrees in the tumor microenvironment, it appears that a high density of T cytotoxic and memory lymphocytes, in a context of Th1 immune orientation in the tumor and its invasion front, provides a prognostic marker of paramount importance for colorectal cancer and more generally all solid tumors. The understanding of the role of immunity in cancer, tailored during one century of intensive research, has led to a complete paradigm shift. In order to show the major impact of this conceptual revolution, we herein retrace through the example of colorectal cancer, how an effective immune test, namely the "Immunoscore", has been developed. We also provide up to date data demonstrating the capacity of the Immunoscore to prognosticate with a better accuracy than the TME classification clinical outcomes and to guide therapeutic strategies.

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A Blueprint to Advance Colorectal Cancer Immunotherapies

Abstract: Immunotherapy is rapidly becoming a standard of care for many cancers.

Cited by 60 publications

References 73 publications

MIR22HG acts as a tumor suppressor via TGFβ/SMAD signaling and facilitates immunotherapy in colorectal cancer

MIR22HG acts as a tumor suppressor via TGFβ/SMAD signaling and facilitates immunotherapy in colorectal cancer

Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice

The Immunoscore in the Clinical Practice of Patients with Colon and Rectal Cancers

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