Collection |

Cancer Immunotherapy

Immunotherapy is the most promising new cancer treatment of the last years. By re-awakening and enhancing the immune system to fight cancer, such strategies have achieved impressive clinical responses. However, many cancer types still do not respond to immunotherapy and many patients do not receive durable benefit, eventually developing resistance.

Broadening the clinical applicability of cancer immunotherapy requires a deep understanding of the molecular and genetic mechanisms that influence whether cancer cells resist or respond. With the ultimate goal to expand the benefits of immunotherapy and find actionable strategies to combat therapeutic resistance, an increasing number of studies are now testing in pre-clinical models different combinations with other therapies, including targeted therapies, and nanoparticle-based approaches. Furthermore, significant efforts are underway to identify reliable predictive biomarkers of response and resistance to immunotherapy such as checkpoint inhibitors.

Our collection, which has been curated by the Cancer editorial  team at Nature Communications, brings together cutting-edge important research in the field of cancer immunotherapy published in our journal. The collection is divided into four research areas; mechanisms of resistance, combination therapies, nanocomplex, and predictors of response. We aim to provide insights on future directions for new therapeutic development in this important area, recognizing the value of bench-based and pre-clinical studies as a first step to translation to the clinic and patient care.

Mechanisms of resistance

  • Nature Communications | Article | open

    Blocking PD-1 function on T cells is thought to be a viable strategy to prevent virus-induced or tumor-induced T cell exhaustion. Here the authors link the zinc-finger transcription factor SALL4 with miR-200c inhibition of PD-L1 expression by hepatocytes in patients with HBV-induced hepatocellular carcinoma.

    • Cheng Sun
    • , Peixiang Lan
    • , Qiuju Han
    • , Mei Huang
    • , Zhihong Zhang
    • , Geliang Xu
    • , Jiaxi Song
    • , Jinyu Wang
    • , Haiming Wei
    • , Jian Zhang
    • , Rui Sun
    • , Cai Zhang
    •  &  Zhigang Tian
  • Nature Communications | Article | open

    Neoantigen load has been associated with tumour immune infiltration. Here, the authors show that while this is true for tumours with recurrent mutations, cancers with recurrent CNAs show neoantigen-independent infiltration driven by cytokine production downstream of the DNA damage sensor ATM.

    • Daniel J. McGrail
    • , Lorenzo Federico
    • , Yongsheng Li
    • , Hui Dai
    • , Yiling Lu
    • , Gordon B. Mills
    • , Song Yi
    • , Shiaw-Yih Lin
    •  &  Nidhi Sahni
  • Nature Communications | Article | open

    A critical determinant of tumor eradication by adoptive immunotherapy is the tumor associated antigen recognized by cytotoxic T lymphocytes. Here the authors generate ex vivo autologous cytotoxic T lymphocytes by exposure to antigens induced by DNA demethylation and report the results of a phase 1 trial of 25 patients with recurrent glioblastoma multiforme with tumor regression in three patients.

    • Alexei F. Kirkin
    • , Karine N. Dzhandzhugazyan
    • , Per Guldberg
    • , Johnny Jon Fang
    • , Rikke S. Andersen
    • , Christina Dahl
    • , Jann Mortensen
    • , Tim Lundby
    • , Aase Wagner
    • , Ian Law
    • , Helle Broholm
    • , Line Madsen
    • , Christer Lundell-Ek
    • , Morten F. Gjerstorff
    • , Henrik J. Ditzel
    • , Martin R. Jensen
    •  &  Walter Fischer
  • Nature Communications | Article | open

    BCL2-inhibitor venetoclax is used to treat relapsed/refractory chronic lymphocytic leukemia (CLL). Here, the authors show the clonal dynamics towards venetoclax resistance by performing whole-exome sequencing of 8 CLL patients undergoing venetoclax treatment.

    • Carmen D. Herling
    • , Nima Abedpour
    • , Jonathan Weiss
    • , Anna Schmitt
    • , Ron Daniel Jachimowicz
    • , Olaf Merkel
    • , Maria Cartolano
    • , Sebastian Oberbeck
    • , Petra Mayer
    • , Valeska Berg
    • , Daniel Thomalla
    • , Nadine Kutsch
    • , Marius Stiefelhagen
    • , Paula Cramer
    • , Clemens-Martin Wendtner
    • , Thorsten Persigehl
    • , Andreas Saleh
    • , Janine Altmüller
    • , Peter Nürnberg
    • , Christian Pallasch
    • , Viktor Achter
    • , Ulrich Lang
    • , Barbara Eichhorst
    • , Roberta Castiglione
    • , Stephan C. Schäfer
    • , Reinhard Büttner
    • , Karl-Anton Kreuzer
    • , Hans Christian Reinhardt
    • , Michael Hallek
    • , Lukas P. Frenzel
    •  &  Martin Peifer
  • Nature Communications | Article | open

    Most melanoma patients do not respond to anti-PD1 therapy. Here, the authors show that TNFα blockade synergizes with anti-PD-1 by preventing anti-PD-1-induced CD8+ T cell death and TIM-3 expression on such cells.

    • Florie Bertrand
    • , Anne Montfort
    • , Elie Marcheteau
    • , Caroline Imbert
    • , Julia Gilhodes
    • , Thomas Filleron
    • , Philippe Rochaix
    • , Nathalie Andrieu-Abadie
    • , Thierry Levade
    • , Nicolas Meyer
    • , Céline Colacios
    •  &  Bruno Ségui
  • Nature Communications | Article | open

    Tumors often develop resistance to radiotherapy. Here the authors show that irradiation leads to a CCR2-dependent infiltration by myeloid derived suppressor cells that promote radio-resistance through inhibition of adaptive immune responses and that the use of CCR2 antibodies in mice reduces such resistance.

    • Hua Liang
    • , Liufu Deng
    • , Yuzhu Hou
    • , Xiangjiao Meng
    • , Xiaona Huang
    • , Enyu Rao
    • , Wenxin Zheng
    • , Helena Mauceri
    • , Matthias Mack
    • , Meng Xu
    • , Yang-Xin Fu
    •  &  Ralph R. Weichselbaum

Combination therapies

  • Nature Communications | Article | open

    A critical determinant of tumor eradication by adoptive immunotherapy is the tumor associated antigen recognized by cytotoxic T lymphocytes. Here the authors generate ex vivo autologous cytotoxic T lymphocytes by exposure to antigens induced by DNA demethylation and report the results of a phase 1 trial of 25 patients with recurrent glioblastoma multiforme with tumor regression in three patients.

    • Alexei F. Kirkin
    • , Karine N. Dzhandzhugazyan
    • , Per Guldberg
    • , Johnny Jon Fang
    • , Rikke S. Andersen
    • , Christina Dahl
    • , Jann Mortensen
    • , Tim Lundby
    • , Aase Wagner
    • , Ian Law
    • , Helle Broholm
    • , Line Madsen
    • , Christer Lundell-Ek
    • , Morten F. Gjerstorff
    • , Henrik J. Ditzel
    • , Martin R. Jensen
    •  &  Walter Fischer
  • Nature Communications | Article | open

    Immune checkpoints blockade (ICB) is a viable anti-cancer strategy. Here the authors show that nuclear receptor NR2F6 acts as an immune checkpoint in T cells and, using mouse models and human T cells, they show NR2F6 inhibition might improve current ICB therapy or work as an alternative therapeutic strategy.

    • Victoria Klepsch
    • , Natascha Hermann-Kleiter
    • , Patricia Do-Dinh
    • , Bojana Jakic
    • , Anne Offermann
    • , Mirjana Efremova
    • , Sieghart Sopper
    • , Dietmar Rieder
    • , Anne Krogsdam
    • , Gabriele Gamerith
    • , Sven Perner
    • , Alexandar Tzankov
    • , Zlatko Trajanoski
    • , Dominik Wolf
    •  &  Gottfried Baier
  • Nature Communications | Article | open

    Antitumor T cells can be inhibited by a TGFβ rich tumor microenvironment. The authors develop bifunctional proteins comprising CTLA-4 or PD-L1 immune checkpoint-targeted antibodies fused to a “TGFβ trap” and show that they counteract tumor immune tolerance and enhance the efficacy of these antibodies.

    • Rajani Ravi
    • , Kimberly A. Noonan
    • , Vui Pham
    • , Rishi Bedi
    • , Alex Zhavoronkov
    • , Ivan V. Ozerov
    • , Eugene Makarev
    • , Artem V. Artemov
    • , Piotr T. Wysocki
    • , Ranee Mehra
    • , Sridhar Nimmagadda
    • , Luigi Marchionni
    • , David Sidransky
    • , Ivan M. Borrello
    • , Evgeny Izumchenko
    •  &  Atul Bedi
  • Nature Communications | Article | open

    XLP-2 syndrome is caused by XIAP mutation. Here the authors show that mouse and human XIAP-deficient regulatory T cells have defective suppressive function as a result of conversion to proinflammatory cytokine producing cells, an effect that can be prevented by blocking the IL-6 receptor.

    • Wan-Chen Hsieh
    • , Tzu-Sheng Hsu
    • , Ya-Jen Chang
    •  &  Ming-Zong Lai
  • Nature Communications | Article | open

    Immunotherapy often fails as a single option treatment in cancer. Here, the authors show that targeting of DNA methyltransferases, such as DNMT1, can potentiate anti-tumor immunity and response to checkpoint inhibition by increasing MHC gene expression and the recruitment of CD8+ T cells.

    • Na Luo
    • , Mellissa J. Nixon
    • , Paula I. Gonzalez-Ericsson
    • , Violeta Sanchez
    • , Susan R. Opalenik
    • , Huili Li
    • , Cynthia A. Zahnow
    • , Michael L. Nickels
    • , Fei Liu
    • , Mohammed N. Tantawy
    • , Melinda E. Sanders
    • , H. Charles Manning
    •  &  Justin M. Balko
  • Nature Communications | Article | open

    Most melanoma patients do not respond to anti-PD1 therapy. Here, the authors show that TNFα blockade synergizes with anti-PD-1 by preventing anti-PD-1-induced CD8+ T cell death and TIM-3 expression on such cells.

    • Florie Bertrand
    • , Anne Montfort
    • , Elie Marcheteau
    • , Caroline Imbert
    • , Julia Gilhodes
    • , Thomas Filleron
    • , Philippe Rochaix
    • , Nathalie Andrieu-Abadie
    • , Thierry Levade
    • , Nicolas Meyer
    • , Céline Colacios
    •  &  Bruno Ségui

Nanocomplex

  • Nature Communications | Article | open

    Immunostimulatory agents used in cancer treatment often elicit serious toxicities, limiting their clinical application. Here, the authors show that the use of liposomes to intravenously deliver surface-anchored IL-2 and anti-CD137 proteins enables anti-cancer immunity and reduces the toxic side effects.

    • Yuan Zhang
    • , Na Li
    • , Heikyung Suh
    •  &  Darrell J. Irvine
  • Nature Communications | Article | open

    Albumin conjugates can enhance drug delivery. Here, the authors repurpose albumin-binding Evans blue to develop nanovaccines that co-deliver adjuvants and tumor neoantigens to antigen-presenting cells in lymph nodes, resulting in potent and durable antitumour immunity in combination immunotherapy.

    • Guizhi Zhu
    • , Geoffrey M. Lynn
    • , Orit Jacobson
    • , Kai Chen
    • , Yi Liu
    • , Huimin Zhang
    • , Ying Ma
    • , Fuwu Zhang
    • , Rui Tian
    • , Qianqian Ni
    • , Siyuan Cheng
    • , Zhantong Wang
    • , Nan Lu
    • , Bryant C. Yung
    • , Zhe Wang
    • , Lixin Lang
    • , Xiao Fu
    • , Albert Jin
    • , Ido D. Weiss
    • , Harshad Vishwasrao
    • , Gang Niu
    • , Hari Shroff
    • , Dennis M. Klinman
    • , Robert A. Seder
    •  &  Xiaoyuan Chen
  • Nature Communications | Article | open

    Pancreatic cancer remains difficult to treat mainly due to the drug delivery challenges posed by a strong stromal component. Here the authors develop nanocarriers that improve drug delivery efficiency and engage the host immune system against the tumor resulting in reduction of tumor growth and metastasis.

    • Jianqin Lu
    • , Xiangsheng Liu
    • , Yu-Pei Liao
    • , Felix Salazar
    • , Bingbing Sun
    • , Wen Jiang
    • , Chong Hyun Chang
    • , Jinhong Jiang
    • , Xiang Wang
    • , Anna M. Wu
    • , Huan Meng
    •  &  Andre E. Nel
  • Nature Communications | Article | open

    Targeted delivery of immunomodulatory compounds to defined subsets of endogenous immune cells may improve the efficacy of combination immunotherapies. Here, the authors use PD-1-targeting nanoparticles containing a TGFβ inhibitor or a TLR7/8 agonist to deliver these payloads to T cells or via T cells to the tumor microenvironment, respectively, leading to anti-tumor efficacy in vivo.

    • Daniela Schmid
    • , Chun Gwon Park
    • , Christina A. Hartl
    • , Nikita Subedi
    • , Adam N. Cartwright
    • , Regina Bou Puerto
    • , Yiran Zheng
    • , James Maiarana
    • , Gordon J. Freeman
    • , Kai W. Wucherpfennig
    • , Darrell J. Irvine
    •  &  Michael S. Goldberg
  • Nature Communications | Article | open

    Nucleic acid nanomedicines are promising for cancer drug delivery. Here, the authors show using a mouse model the tumor immunotherapeutic efficacy of nanovaccines based on intertwining DNA-RNA nanocapsules loaded with DNA CpG, Stat3-silencing short hairpin RNA and tumor-specific peptide neoantigens.

    • Guizhi Zhu
    • , Lei Mei
    • , Harshad D. Vishwasrao
    • , Orit Jacobson
    • , Zhantong Wang
    • , Yijing Liu
    • , Bryant C. Yung
    • , Xiao Fu
    • , Albert Jin
    • , Gang Niu
    • , Qin Wang
    • , Fuwu Zhang
    • , Hari Shroff
    •  &  Xiaoyuan Chen
  • Nature Communications | Article | open

    MnO2 nanostructures are promising TME-responsive theranostic agents in cancer. Here, the authors develop a nano-platform based on hollow H-MnO2 nanoshells able to modulate the tissue microenvironment, release a drug and inhibit tumor growth alone or in combination with check-point blockade therapy.

    • Guangbao Yang
    • , Ligeng Xu
    • , Yu Chao
    • , Jun Xu
    • , Xiaoqi Sun
    • , Yifan Wu
    • , Rui Peng
    •  &  Zhuang Liu

Predictors of response

  • Nature Communications | Article | open

    Epithelial ovarian cancer (EOC) has low mutational load. Here the authors analyze circulating and tumor-infiltrating lymphocytes (TILs) from 19 EOC patients and report frequent recovery of neo-antigen-reactive T cells from both compartments but with distinct TCR repertoires that have higher affinity in TILs.

    • Sara Bobisse
    • , Raphael Genolet
    • , Annalisa Roberti
    • , Janos L. Tanyi
    • , Julien Racle
    • , Brian J. Stevenson
    • , Christian Iseli
    • , Alexandra Michel
    • , Marie-Aude Le Bitoux
    • , Philippe Guillaume
    • , Julien Schmidt
    • , Valentina Bianchi
    • , Denarda Dangaj
    • , Craig Fenwick
    • , Laurent Derré
    • , Ioannis Xenarios
    • , Olivier Michielin
    • , Pedro Romero
    • , Dimitri S. Monos
    • , Vincent Zoete
    • , David Gfeller
    • , Lana E. Kandalaft
    • , George Coukos
    •  &  Alexandre Harari
  • Nature Communications | Article | open

    There is an urgent need to identify predictive markers for selecting responders to immunotherapy. Here, the authors describe a transcriptional predictor of immunotherapy response and assess it in genomic data from ~ 10,000 human tissues across 30 different cancer types.

    • Chan-Young Ock
    • , Jun-Eul Hwang
    • , Bhumsuk Keam
    • , Sang-Bae Kim
    • , Jae-Jun Shim
    • , Hee-Jin Jang
    • , Sarang Park
    • , Bo Hwa Sohn
    • , Minse Cha
    • , Jaffer A. Ajani
    • , Scott Kopetz
    • , Keun-Wook Lee
    • , Tae Min Kim
    • , Dae Seog Heo
    •  &  Ju-Seog Lee
  • Nature Communications | Article | open

    Adoptive T cell therapy (ACT) has yielded high response rates in melanoma, however 50–60% of patients experience no clinical benefit. Here, the authors identify predictive biomarkers, high non-synonymous mutation and high expressed neoantigen load, that associate with clinical benefit in ACT melanoma patients.

    • Martin Lauss
    • , Marco Donia
    • , Katja Harbst
    • , Rikke Andersen
    • , Shamik Mitra
    • , Frida Rosengren
    • , Maryem Salim
    • , Johan Vallon-Christersson
    • , Therese Törngren
    • , Anders Kvist
    • , Markus Ringnér
    • , Inge Marie Svane
    •  &  Göran Jönsson
  • Nature Communications | Article | open

    IFNγ secretion by CD8+ T cells is critical for immunotherapy efficacy. In this study, the authors show that melanoma patients can become resistant to immunotherapy by acquiring chromosomal alterations and subsequent inactivating mutations in genes of the IFNγ signalling cascade, most often JAK1 or JAK2.

    • Antje Sucker
    • , Fang Zhao
    • , Natalia Pieper
    • , Christina Heeke
    • , Raffaela Maltaner
    • , Nadine Stadtler
    • , Birgit Real
    • , Nicola Bielefeld
    • , Sebastian Howe
    • , Benjamin Weide
    • , Ralf Gutzmer
    • , Jochen Utikal
    • , Carmen Loquai
    • , Helen Gogas
    • , Ludger Klein-Hitpass
    • , Michael Zeschnigk
    • , Astrid M. Westendorf
    • , Mirko Trilling
    • , Susanne Horn
    • , Bastian Schilling
    • , Dirk Schadendorf
    • , Klaus G. Griewank
    •  &  Annette Paschen
  • Nature Communications | Article | open

    The clinical management of metastatic melanoma requires predictors of the response to checkpoint blockade. Here, the authors use immunological assays to identify potential prognostic/predictive biomarkers in circulating blood cells and in tumor-infiltrating lymphocytes from patients with resected stage III melanoma.

    • N. Jacquelot
    • , M. P. Roberti
    • , D. P. Enot
    • , S. Rusakiewicz
    • , N. Ternès
    • , S. Jegou
    • , D. M. Woods
    • , A. L. Sodré
    • , M. Hansen
    • , Y. Meirow
    • , M. Sade-Feldman
    • , A. Burra
    • , S. S. Kwek
    • , C. Flament
    • , M. Messaoudene
    • , C. P. M. Duong
    • , L. Chen
    • , B. S. Kwon
    • , A. C. Anderson
    • , V. K. Kuchroo
    • , B. Weide
    • , F. Aubin
    • , C. Borg
    • , S. Dalle
    • , O. Beatrix
    • , M. Ayyoub
    • , B. Balme
    • , G. Tomasic
    • , A. M. Di Giacomo
    • , M. Maio
    • , D. Schadendorf
    • , I. Melero
    • , B. Dréno
    • , A. Khammari
    • , R. Dummer
    • , M. Levesque
    • , Y. Koguchi
    • , L. Fong
    • , M. Lotem
    • , M. Baniyash
    • , H. Schmidt
    • , I. M. Svane
    • , G. Kroemer
    • , A. Marabelle
    • , S. Michiels
    • , A. Cavalcanti
    • , M. J. Smyth
    • , J. S. Weber
    • , A. M. Eggermont
    •  &  L. Zitvogel
  • Nature Communications | Article | open

    PD-L1, the ligand for T-cell inhibitory receptor PD-1, can be expressed by various cell types in the tumour microenvironment. Here, the authors show that, in mouse models, the expression of PD-L1 from both cancerous and normal host immune cells is important for suppressing anti-tumour immune responses.

    • Janet Lau
    • , Jeanne Cheung
    • , Armando Navarro
    • , Steve Lianoglou
    • , Benjamin Haley
    • , Klara Totpal
    • , Laura Sanders
    • , Hartmut Koeppen
    • , Patrick Caplazi
    • , Jacqueline McBride
    • , Henry Chiu
    • , Rebecca Hong
    • , Jane Grogan
    • , Vincent Javinal
    • , Robert Yauch
    • , Bryan Irving
    • , Marcia Belvin
    • , Ira Mellman
    • , Jeong M. Kim
    •  &  Maike Schmidt