May 21, 2022

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Nature Immunology: “Heating” a “Cold” Tumor into a “Hot” Tumor

Nature Immunology: “Heating” a “Cold” Tumor into a “Hot” Tumor


Nature Immunology: “Heating” a “Cold” Tumor into a “Hot” Tumor: The Promoting Role of Type 3 Innate Lymphocytes in the Antitumor Response.

Immune checkpoint blockade therapy ( ICB ) triggers durable antitumor immune responses, but tumors lacking lymphocyte infiltration (“cold” tumors) are resistant to ICB therapy.

Conversely, increasing T-cell infiltration of cold tumors might enhance their sensitivity to ICB therapy.

Type 3 innate lymphocytes ( ILC3s ) include ILC3s expressing natural cytotoxicity receptor ( NCR ) , chemokine receptor 6 (CCR6) , and lymphoid tissue inducer ( LTi ) .

However, the antitumor roles of LTi are contradictory, as accumulation of ILC3s is associated with poor outcomes in breast and colorectal cancer, but opposite in non-small cell lung cancer ( NSCLC ) and melanoma [1-4] .


It should be noted that in NSCLC, ILC3s were positively correlated with the presence of tertiary lymphoid structures, indicating that ILC3s may have lymphocyte recruitment ability [5].

Furthermore, the chemokine CCL20 is normally expressed at low levels but can be strongly induced by pro-inflammatory signals such as TNF and IL-1β.

CCL20 is a unique ligand for CCR6, thus expression of CCR6 on the surface of ILC3s causes these cells to be recruited by CCL20.

From this information, it can be inferred that a CCL20- and IL-1β-enriched environment may have activated CCR6+ILC3s.


The combination of cisplatin-based chemotherapy and ICB is the standard first-line treatment for metastatic NSCLC, but the mechanism of synergy between the two remains to be determined .

The tumor transforms into a “hot” tumor that is more abundant in immune cell infiltration to function.


On January 31, 2022, the team of Mélanie Bruchard from Equipe Labellisée Ligue Contre le Cancer, France , published an article titled “Recruitment and activation of type 3 innate lymphoid cells promote antitumor immune responses” in the journal Nature Immunology .

Using a tumor mouse model, it was found that after cisplatin administration, the tumor site can produce CCL20 and IL-1β, leading to the recruitment and activation of ILC3s, and ILC3s are responsible for recruiting CD4+ and CD8+ T lymphocytes to the tumor through the production of CXCL10, thereby improving anti-tumor Immunity and response to ICB. This finding is crucial for explaining the antitumor mechanism of cisplatin.



Nature Immunology: "Heating" a "Cold" Tumor into a "Hot" Tumor: The Promoting Role of Type 3 Innate Lymphocytes in the Antitumor Response.



The researchers selected mouse models of “cold” tumors (such as TC-1 lung cancer, 4T1 breast cancer) and “hot” tumors (such as MC38 colon cancer) to complete the experiments.

Intratumoral immune cell populations were analyzed by flow cytometry after cisplatin administration in the TC-1 model, and it was found that ILC3s were the first cell type to accumulate in tumors, while CCR6+ILC3 were the most common subset, not only that , the authors also observed a correlation between ILC3 accumulation and CD8+ and CD4+ T cell accumulation.

To demonstrate whether CCR6+ILC3 has an effect on the antitumor effect of cisplatin, the authors used two RORγt inhibitors, digoxin and GSK805, in TC-1 and 4T1 models, the former depletes both ILC3 and Th17 cells, while the latter only depletes Th17 cells.

The administration of digoxin can significantly attenuate the recruitment of other immune cells induced by cisplatin in the later stage and reduce the antitumor effect, while the administration of GSK805 did not have any effect on tumor growth, emphasizing that ILC3 is crucial for the antitumor effect of cisplatin.


The most expressed checkpoint inhibitor target on T cells in the TC-1 model was CTLA-4, and we treated TC-1 tumors with a combination of cisplatin and anti-CTLA-4 to investigate the effect of ILC3 on ICB antitumor efficacy.

Combination therapy lost its inhibitory effect on TC-1 tumor growth following digoxin administration.

Similarly, depletion of ILC3s significantly attenuated the combined anti-PD-1 and anti-CTLA-4 efficacy in the thermal tumor model MC38 mice.

These findings highlight that ILC3s are both essential in the anti-cold-tumor efficacy of ICBs.


So how does ILC3 cause an increase in the number of immune cells at the tumor site after cisplatin treatment?

To this end, the authors performed scRNA-seq on TC-1 tumor-sorted lymphocytes and found that after cisplatin treatment, ILC3 expressed high levels of the chemokine CXCL10, which is known to favor lymphocyte recruitment.

The control of tumor growth by cisplatin was significantly reduced if an antibody against the CXCL10 receptor was used in vivo, while the addition of digoxin at this time did not further reduce efficacy.

In addition, the blocking effect of the antibody also reduced immune cell infiltration other than the ILC3 population.

These data suggest that ILC3 recruits lymphocytes by expressing CXCL10 and can convert cold tumors to hot tumors.


However, cisplatin alone did not enhance CCR6+ILC3 proliferation.

The authors further screened and kinetically analyzed cytokines and chemokines in tumors after treatment, and found that cisplatin could induce CCL20, which acts as a ligand for CCR6, which is also a chemokine for CCR6-expressing cells.

Ex vivo analysis also allowed the researchers to confirm that tumor cells were the major producers of CCL20 after cisplatin treatment and were the only cell type induced.

If a CCL20 blocking antibody is used in TC-1 mice, the number of CCR6+ ILC3 and the subsequent recruitment of immune cells such as CD4+ and CD8+ T cells can be greatly reduced, with a concomitant decrease in the efficacy of cisplatin. Similar effects were also identified in the MC38 mouse model.


In addition, the authors also found that IL-1β increased in tumors after cisplatin treatment, and scRNA-seq also showed enrichment of IL-1R in the CCR6+ILC3 cluster, suggesting that cisplatin induces their activation in an IL-1β-dependent manner .

Inhibition of IL-1β using IL-1RA resulted in the activation and accumulation of ILC3 and decreased production of CXCL10. Considering the importance of CCL20 and IL-1β, the authors co-injected them into TC-1 mice.

The results showed a significant increase in the number of CCR6+ILC3, CD8+, and CD4+ T cells in the tumor, which also hindered tumor growth.

If both were injected into the tumors of MC38 mice, the tumor response to ICB could be significantly improved. But if digoxin is used, all of the above benefits are eliminated.

Thus, the critical roles of CCL20 and IL-1β in the recruitment and activation of ILC3 and tumor immune infiltration.


In conclusion, this study explains the antitumor molecular mechanism of cisplatin, revealing the important role of ILC3 cells in shaping tumor immune infiltration and antitumor efficacy after chemotherapy.

In addition, combination therapy with ILC3 or CCL20 and IL-1β may be an effective strategy to convert “cold” tumors with poor T-cell infiltration into “hot” tumors responsive to ICB.


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1. Irshad, S. et al. RORγt+ innate lymphoid cells promote lymph node metastasis of breast cancers . Cancer Res . 77, 1083–1096 (2017).

2. Kirchberger, S. et al. Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J. Exp. Med . 210, 917–931 (2013).

3. Eisenring, M., vom Berg, J., Kristiansen, G., Saller, E. & Becher, B. IL-12 initiates tumor rejection via lymphoid tissue-inducer cells bearing the natural cytotoxicity receptor NKp46. Nat. Immunol . 11, 1030–1038 (2010).

4. Nussbaum, K. et al. Tissue microenvironment dictates the fate and tumor-suppressive function of type 3 ILCs. J. Exp. Med . 214, 2331–2347 (2017).

5. Dieu-Nosjean, M.-C. et al. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J. Clin. Oncol . 26, 4410–4417 (2008).

Nature Immunology: “Heating” a “Cold” Tumor into a “Hot” Tumor: The Promoting Role of Type 3 Innate Lymphocytes in the Antitumor Response.

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