Overcoming Primary and Acquired Resistance to Anti-PD-L1 Therapy by Induction and Activation of Tumor-residing CDC1s

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Oct 28

PMID 33110069

Citations 66

Authors

Takaaki Oba

Mark D Long

Tibor Keler

Henry C Marsh

Hans Minderman

Scott I Abrams

Song Liu

Fumito Ito

Affiliations

Soon will be listed here.

Abstract

The ability of cancer cells to ensure T-cell exclusion from the tumor microenvironment is a significant mechanism of resistance to anti-PD-1/PD-L1 therapy. Evidence indicates crucial roles of Batf3-dependent conventional type-1 dendritic cells (cDC1s) for inducing antitumor T-cell immunity; however, strategies to maximize cDC1 engagement remain elusive. Here, using multiple orthotopic tumor mouse models resistant to anti-PD-L1-therapy, we are testing the hypothesis that in situ induction and activation of tumor-residing cDC1s overcomes poor T-cell infiltration. In situ immunomodulation with Flt3L, radiotherapy, and TLR3/CD40 stimulation induces an influx of stem-like Tcf1 Slamf6 CD8 T cells, triggers regression not only of primary, but also untreated distant tumors, and renders tumors responsive to anti-PD-L1 therapy. Furthermore, serial in situ immunomodulation (ISIM) reshapes repertoires of intratumoral T cells, overcomes acquired resistance to anti-PD-L1 therapy, and establishes tumor-specific immunological memory. These findings provide new insights into cDC1 biology as a critical determinant to overcome mechanisms of intratumoral T-cell exclusion.

Citing Articles

Comprehensive immunophenotyping reveals distinct tumor microenvironment alterations in anti-PD-1 sensitive and resistant syngeneic mouse model.

Inoue H, Hamasaki T, Inoue K, Nakao A, Ebi N, Minomo H Sci Rep. 2025; 15(1):8311.

PMID: 40064915 PMC: 11894063. DOI: 10.1038/s41598-025-91979-w.

Dendritic cell maturation in cancer.

Moon C, Belabed M, Park M, Mattiuz R, Puleston D, Merad M Nat Rev Cancer. 2025; .

PMID: 39920276 DOI: 10.1038/s41568-024-00787-3.

FBXO31-mediated ubiquitination of OGT maintains O-GlcNAcylation homeostasis to restrain endometrial malignancy.

Zhang N, Meng Y, Mao S, Ni H, Huang C, Shen L Nat Commun. 2025; 16(1):1274.

PMID: 39894887 PMC: 11788441. DOI: 10.1038/s41467-025-56633-z.

Cross-priming in cancer immunology and immunotherapy.

Luri-Rey C, Teijeira A, Wculek S, de Andrea C, Herrero C, Lopez-Janeiro A Nat Rev Cancer. 2025; .

PMID: 39881005 DOI: 10.1038/s41568-024-00785-5.

Divergent transcriptional states and kinetics of circulating tumor-infiltrating lymphocyte repertoires with highly homologous T-cell receptor sequences in a patient during immunotherapy.

Kajihara R, Long M, Hoki T, Chen H, Yamauchi T, Kanemaru H J Immunother Cancer. 2025; 13(1).

PMID: 39863301 PMC: 11784231. DOI: 10.1136/jitc-2024-010092.

References

Raghu D, Xue H, Mielke L . Control of Lymphocyte Fate, Infection, and Tumor Immunity by TCF-1. Trends Immunol. 2019; 40(12):1149-1162. DOI: 10.1016/j.it.2019.10.006. View

Nimanong S, Ostroumov D, Wingerath J, Knocke S, Woller N, Gurlevik E . CD40 Signaling Drives Potent Cellular Immune Responses in Heterologous Cancer Vaccinations. Cancer Res. 2017; 77(8):1918-1926. DOI: 10.1158/0008-5472.CAN-16-2089. View

Belz G, Behrens G, Smith C, Miller J, Jones C, Lejon K . The CD8alpha(+) dendritic cell is responsible for inducing peripheral self-tolerance to tissue-associated antigens. J Exp Med. 2002; 196(8):1099-104. PMC: 2194045. DOI: 10.1084/jem.20020861. View

Stewart T, Liewehr D, Steinberg S, Greeneltch K, Abrams S . Modulating the expression of IFN regulatory factor 8 alters the protumorigenic behavior of CD11b+Gr-1+ myeloid cells. J Immunol. 2009; 183(1):117-28. PMC: 2744444. DOI: 10.4049/jimmunol.0804132. View

Ahonen C, Doxsee C, McGurran S, Riter T, Wade W, Barth R . Combined TLR and CD40 triggering induces potent CD8+ T cell expansion with variable dependence on type I IFN. J Exp Med. 2004; 199(6):775-84. PMC: 2212721. DOI: 10.1084/jem.20031591. View

Sanchez-Paulete A, Cueto F, Martinez-Lopez M, Labiano S, Morales-Kastresana A, Rodriguez-Ruiz M . Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells. Cancer Discov. 2015; 6(1):71-9. PMC: 5036540. DOI: 10.1158/2159-8290.CD-15-0510. View

Spranger S, Bao R, Gajewski T . Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature. 2015; 523(7559):231-5. DOI: 10.1038/nature14404. View

Sharma P, Hu-Lieskovan S, Wargo J, Ribas A . Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell. 2017; 168(4):707-723. PMC: 5391692. DOI: 10.1016/j.cell.2017.01.017. View

Spranger S, Dai D, Horton B, Gajewski T . Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy. Cancer Cell. 2017; 31(5):711-723.e4. PMC: 5650691. DOI: 10.1016/j.ccell.2017.04.003. View

10.

Scott A, Dundar F, Zumbo P, Chandran S, Klebanoff C, Shakiba M . TOX is a critical regulator of tumour-specific T cell differentiation. Nature. 2019; 571(7764):270-274. PMC: 7698992. DOI: 10.1038/s41586-019-1324-y. View

11.

Aran D, Looney A, Liu L, Wu E, Fong V, Hsu A . Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat Immunol. 2019; 20(2):163-172. PMC: 6340744. DOI: 10.1038/s41590-018-0276-y. View

12.

Kratchmarov R, Magun A, Reiner S . TCF1 expression marks self-renewing human CD8 T cells. Blood Adv. 2018; 2(14):1685-1690. PMC: 6058237. DOI: 10.1182/bloodadvances.2018016279. View

13.

Hammerich L, Marron T, Upadhyay R, Svensson-Arvelund J, Dhainaut M, Hussein S . Systemic clinical tumor regressions and potentiation of PD1 blockade with in situ vaccination. Nat Med. 2019; 25(5):814-824. DOI: 10.1038/s41591-019-0410-x. View

14.

Engblom C, Pfirschke C, Pittet M . The role of myeloid cells in cancer therapies. Nat Rev Cancer. 2016; 16(7):447-62. DOI: 10.1038/nrc.2016.54. View

15.

Seo H, Chen J, Gonzalez-Avalos E, Samaniego-Castruita D, Das A, Wang Y . TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8 T cell exhaustion. Proc Natl Acad Sci U S A. 2019; 116(25):12410-12415. PMC: 6589758. DOI: 10.1073/pnas.1905675116. View

16.

Yost K, Satpathy A, Wells D, Qi Y, Wang C, Kageyama R . Clonal replacement of tumor-specific T cells following PD-1 blockade. Nat Med. 2019; 25(8):1251-1259. PMC: 6689255. DOI: 10.1038/s41591-019-0522-3. View

17.

Scarlett U, Cubillos-Ruiz J, Nesbeth Y, Martinez D, Engle X, Gewirtz A . In situ stimulation of CD40 and Toll-like receptor 3 transforms ovarian cancer-infiltrating dendritic cells from immunosuppressive to immunostimulatory cells. Cancer Res. 2009; 69(18):7329-37. PMC: 2754806. DOI: 10.1158/0008-5472.CAN-09-0835. View

18.

Miller B, Sen D, Al Abosy R, Bi K, Virkud Y, LaFleur M . Subsets of exhausted CD8 T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol. 2019; 20(3):326-336. PMC: 6673650. DOI: 10.1038/s41590-019-0312-6. View

19.

Diehl L, den Boer A, Schoenberger S, van der Voort E, Schumacher T, Melief C . CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy. Nat Med. 1999; 5(7):774-9. DOI: 10.1038/10495. View

20.

Weichselbaum R, Liang H, Deng L, Fu Y . Radiotherapy and immunotherapy: a beneficial liaison?. Nat Rev Clin Oncol. 2017; 14(6):365-379. DOI: 10.1038/nrclinonc.2016.211. View