Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Molecular Diagnostics

Checkpoint inhibitors in a marriage: consented or arranged?


There is currently a strong development of therapeutic combinations with checkpoint inhibitors (CPIs). The most promising combinations with CPIs concern anti-angiogenic agents and BRAF/MEK inhibitors. The timing of the initiation of the combination should be particularly well investigated for chemotherapy. Combinations between CPIs raise questions about risk/benefit ratio and overall clinical activity.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: A decade of hope with CPIs: from reality to new challenges.


  1. Steinberg SM, Zhang P, Malik BT, Boni A, Shabaneh TB, Byrne KT, et al. BRAF inhibition alleviates immune suppression in murine autochthonous melanoma. Cancer Immunol Res. 2014;2:1044–50.

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  2. Lee WS, Yang H, Chon HJ, Kim C. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Exp Mol Med. 2020;52:1475–85.

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  3. Ferris RL, Lenz HJ, Trotta AM, García-Foncillas J, Schulten J, Audhuy F, et al. Rationale for combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors: Harnessing innate and adaptive immunity through IgG1 isotype immune effector stimulation. Cancer Treat Rev. 2018;63:48–60.

    CAS  Article  PubMed  Google Scholar 

  4. Fountzilas C, Bajor DL, Mukherjee S, Saltzman J, Witkiewicz AK, Maguire O, et al. Phase Ib/II study of cetuximab plus pembrolizumab in patients with advanced RAS wild-type colorectal cancer. Clin Cancer Res. 2021;27:6726–36.

    CAS  Article  PubMed  Google Scholar 

  5. Pfirschke C, Engblom C, Rickelt S, Cortez-Retamozo V, Garris C, Pucci F, et al. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity. 2016;44:343–54.

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  6. Okita R, Maeda A, Shimizu K, Nojima Y, Saisho S, Nakata M. Effect of platinum-based chemotherapy on the expression of natural killer group 2 member D ligands, programmed cell death-1 ligand 1 and HLA class i in non-small cell lung cancer. Oncol Rep. 2019;42:839–48.

    CAS  Article  PubMed  Google Scholar 

  7. Long GV, Robert C, Butler MO, Couture F, Carlino MS, O’Day S, et al. Standard-dose pembrolizumab plus alternate-dose ipilimumab in advanced melanoma: KEYNOTE-029 cohort 1C, a phase 2 randomized study of two dosing schedules. Clin Cancer Res. 2021;27:5280–8.

    CAS  Article  PubMed  Google Scholar 

  8. Goel S, DeCristo MJ, Watt AC, BrinJones H, Sceneay J, Li BB, et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017;548:471–5.

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  9. Zhang J, Bu X, Wang H, Zhu Y, Geng Y, Nihira NT, et al. Cyclin D–CDK4 kinase destabilizes PD-L1 via cullin 3–SPOP to control cancer immune surveillance. Nature. 2018;553:91–5.

    CAS  Article  PubMed  Google Scholar 

  10. Shen J, Zhao W, Ju Z, Wang L, Peng Y, Labrie M, et al. PARPI triggers the STING-dependent immune response and enhances the therapeutic efficacy of immune checkpoint blockade independent of BRCANEss. Cancer Res. 2019;79:311–9.

    CAS  Article  PubMed  Google Scholar 

  11. Lucibello G, Mograbi B, Milano G, Hofman P, Brest P. PD-L1 regulation revisited: impact on immunotherapeutic strategies. Trends Mol Med. 2021;27:1–14.

    CAS  Article  Google Scholar 

  12. Palmer AC, Izar B, Hwangbo H, Sorger PK. Predictable clinical benefits without evidence of synergy in trials of combination therapies with immune-checkpoint inhibitors. Clin Cancer Res. 2022;28:368–77.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Meric-Bernstam F, Larkin J, Tabernero J, Bonini C. Enhancing anti-tumour efficacy with immunotherapy combinations. Lancet. 2021;397:1010–22.

    CAS  Article  PubMed  Google Scholar 

Download references


We would like to thank the UCA Office of International Scientific Visibility for comments on the English version of the manuscript.


Funding is acknowledged from the French Government (Agence Nationale de Recherche, ANR) through the ‘Investments for the Future’ LABEX SIGNALIFE (ANR-11-LABX-0028-01 and IDEX UCAJedi ANR-15-IDEX-01) and [AD-ME project R19162DD]; CANC’AIR Genexposomic project, Canceropole PACA; DREAL PACA, ARS PACA, Région Sud, INSERM cancer; INCA Plan Cancer; Children Medical Safety Research Institute (CMSRI, Vaccinophagy project R17033DJA).

Author information

Authors and Affiliations



PB, BM, CB, PH and GM participated in writing the article. PB, BM and GM participated in the preparation of the figure. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Gerard Milano.

Ethics declarations

Competing interests

PB and BM declare no financial ties with any organisation that might have an interest in the submitted work over the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work. GM has received honoraria from MERCK, Bristol Myers Squibb (BMS) for lectures specifically on the covered subject. PH has received honoraria from AstraZeneca, BMS, MSD, Lilly, Bayer, Pfizer, ThermoFisher, Roche, Illumina, Novartis, Biocartis, Janssen and Abbvie for lectures, consulting fees and membership on their advisory board.

Ethics approval and consent to participate

Not applicable for this comment.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Brest, P., Refae, S., Mograbi, B. et al. Checkpoint inhibitors in a marriage: consented or arranged?. Br J Cancer 126, 1834–1836 (2022).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


Quick links