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Oncoimmunology. 2017; 6(7): e1325982.
Published online 2017 May 12. doi:  10.1080/2162402X.2017.1325982
PMCID: PMC5543902

PD-L1 immune suppression in cancer: Tumor cells or host cells?

ABSTRACT

Four recent publications reported the role of PD-L1 expression on host versus malignant cells within the tumor for PD-1/PD-L1 checkpoint blockade therapy. All four research groups harmoniously report: PD-L1 expressed by both host as well as tumor cells are capable of suppressing T cell functions. Thus, checkpoint therapy can be effective, if malignant cells do not express PD-L1.

Keywords: Biomarker, checkpoint blockade, expression, immunotherapy, PD-1, PD-L1

Within a time window of 2 mo in early 2017, four independent research groups published papers in high impact journals advocating a similar message using gene silencing technologies in vivo. All groups investigated the role of PD-L1 expression on different cell types within the tumor-microenvironment, in terms of T cell inhibition and/or immune-checkpoint blockade therapy (Fig. 1). Not only is this a tribute to the importance of the PD-1/PD-L1 axis in tumor immunology, but also illustrates the speed at which the oncoimmunology field is progressing.

Figure 1.
PD-L1 expression on tumor cells and host cells jointly support tumor outgrowth. Left: in a typical immunogenic tumor, both tumor cells and intratumoral host cells express PD-L1, resulting in progressive tumor growth. Middle: experimental genetic deletion ...

In Cancer Immunology Research, Noguchi et al. used two variants of an MCA-induced mouse tumor model that either grow progressively or regress spontaneously.1 By overexpressing or knocking out PD-L1, using CRISPR-Cas9, they described how PD-L1 on tumor cells determines whether tumors progress or regress, by inhibiting the antitumor T cell response. Tumors that were otherwise too immunogenic to establish, were growing out rapidly by overexpression of PD-L1. Conversely, tumors growing out in immune competent mice were spontaneously eradicated or slowed in their tumor-outgrowth when PD-L1 was knocked out from tumor cells. In all these cases, blocking PD-L1 with a therapeutic antibody had additional effect, indicating a role of PD-L1 on stromal cells.

In Nature Communications, Lau et al. used both PD-L1−/− tumor cells, generated with CRISPR-Cas9, and a newly generated PD-L1 knockout mouse as a host, to study T cell inhibition by PD-L1 in two commonly used mouse tumor models, MC38 and CT26.2 PD-L1 knockout variants of these tumors spontaneously regress or grow slower than WT counterparts, while therapeutic PD-L1 blockade further extends survival, indicating an additive role of PD-L1 on both tumor and host cells. Gene expression analysis showed the strongest enrichment for T cell immunity-related genes when PD-L1 was lacking on both tumor cells and host cells. The authors describe several alternative immune escape mechanisms in outgrowing PD-L1 knockout tumors, including reduced MHC-I expression and increased PD-L2 expression.

In the Journal of Experimental Medicine, Juneja et al. emphasize that while both tumor and host cell PD-L1 expression can play a crucial role in T cell suppression and response to blockade therapy, their exact relative contribution is context-dependent, as it differed per tumor model in their experiments.3 The authors used three different mouse tumor models in host mice deficient for either PD-1 or for both PD-L1 and PD-L2, as compared with WT hosts. Whereas B16 and BRAF.PTEN tumors grew slower in both PD-1 deficient mice and PD-L1 deficient mice, MC38 tumors only benefited from the absence of host PD-1, indicating no relevant role for host PD-L1 in MC38 tumor growth. The strong effect of therapeutic PD-L1 blockade was therefore largely dependent on tumor cell-expressed PD-L1, and could be mimicked by knocking out PD-L1 selectively on tumor cells. The authors further argue that PD-1 expression on T cells in tumors or tumor-draining lymph nodes may well reflect recent activation and not necessarily a dysfunctional state, especially when PD-1 ligands are lacking or blocked at the target site.

Finally, in OncoImmunology, we have described a non-redundant role of PD-L1 expression on tumor cells and host cells.4 Using CRISPR-Cas9 technology, we created PD-L1 knockout variants of MC38 and CT26, the two most widely used pre-clinical tumor models in tumor immunotherapy research, which both grew out more slowly than WT tumors. In straight-forward experiments, we show that blocking PD-L1 or PD-1 with therapeutic antibodies still has tumor-eradicating effects on these tumors, indicating an additional role for PD-L1 on immune infiltrating cells within the tumor microenvironment. T cell depletion studies emphasized the crucial role of CD8 T cells in the antitumor effects of both the lack of PD-L1 on tumor cells and of blocking antibody therapy.

Each study reveals, from a different angle, that PD-L1 on tumor and host cells is involved in suppressing the antitumor T cell response. All manuscripts show that in immunocompetent mice, tumor cells grow out slower or regress spontaneously when PD-L1 is genetically knocked out, an effect mediated by T-cell responses (Fig. 1). There was, however, a minor discrepancy between the studies. Juneja et al. concluded that PD-L1 expression on MC38 tumor cells was fully responsible for inhibiting antitumor T cell responses, with no additional role for PD-L1 on host cells, whereas the papers of Lau and ourselves both showed that PD-L1 blocking antibody therapy of MC38 PD-L1 knockout tumors still gives a therapeutic response. These two conclusions were based on slightly different experimental setups, which may explain the differences. In Lau et al. and our paper, the role of host PD-L1 expression was shown by therapeutic PD-L1 blockade in WT mice-bearing PD-L1 knockout MC38 tumors. Although in Juneja's study, outgrowth of untreated PD-L1 knockout MC38 tumors was much more hampered compared with the other studies, an additional role of PD-L1 on host cells cannot be fully excluded, since they did not treat these mice with PD-L1 blocking antibody.

The knowledge gained by the four studies contributes greatly to our understanding of tumor immunology. By investigating the topic from different angles and using various techniques and pre-clinical models, the four studies complement and validate each other. The combined outcomes signify an important biomarker for the use of PD-1 and PD-L1 blocking antibody therapeutics. Expression of PD-L1 within the tumor, but not necessarily on tumor cells, is sufficient for a therapeutic effect of PD-1/PD-L1 blocking antibodies, meaning that absence of PD-L1 expression on tumor cells does not disqualify patients for treatment.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

References

1. Noguchi T, Ward JP, Gubin MM, Arthur CD, Lee SH, Hundal J, Selby MJ, Graziano RF, Mardis ER, Korman AJ et al. Temporally distinct PD-L1 expression by tumor and host cells contributes to immune escape. Cancer Immunol Res 2017; 5:106-117; PMID:28073774; https://doi.org/10.1158/2326-6066.CIR-16-0391 [PMC free article] [PubMed] [Cross Ref]
2. Lau J, Cheung J, Navarro A, Lianoglou S, Haley B, Totpal K, Sanders L, Koeppen H, Caplazi P, McBride J et al. Tumour and host cell PD-L1 is required to mediate suppression of anti-tumour immunity in mice. Nat Commun 2017; 8:14572; PMID: 28220772; https://doi.org/10.1038/ncomms14572 [PMC free article] [PubMed] [Cross Ref]
3. Juneja VR, McGuire KA, Manguso RT, LaFleur MW, Collins N, Haining WN, Freeman GJ, Sharpe AH PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity. J Exp Med 2017; 214:895-904; PMID:28302645; https://doi.org/10.1084/jem.20160801 [PMC free article] [PubMed] [Cross Ref]
4. Kleinovink JW, Marijt KA, Schoonderwoerd MJA, van Hall T, Ossendorp F, Fransen MF. PD-L1 expression on malignant cells is no prerequisite for checkpoint therapy. Oncoimmunology 2017; e1294299; PMID:28507803; https://doi.org/10.1080/2162402X.2017.1294299 [PMC free article] [PubMed] [Cross Ref]

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