Unique anti-tumor functions of IFNg vs. IL-17 producing CD8 cells

The anti-tumor power of IFNγ-producing CD4⁺ T_H1 cells and CD8⁺ T_C1 cells is well established. The role of IL-17 producing CD4⁺ (T_H17) and CD8⁺ T cells (T_C17) is less clear — different studies have found these cells can either inhibit or promote tumor growth. Context seems to be the key factor in whether IL-17-producing T cell subsets help or hurt anti-tumor immunity.

Comparing T_C1 and T_C17 Cells in a Melanoma Model

In the February 15, 2013 issue of The Journal of Immunology, Yu et al. compared how adoptively transferred tumor-specific T_C1 and T_C17 cells controlled tumor growth in mice. Here’s how the experiment worked:

• Researchers took anti-gp100 T cells from Pmel-1 TCR transgenic mice.
• They polarized these cells ex-vivo into either T_C1 or T_C17 phenotypes.
• They transferred the cells into mice with luciferase-expressing B16F10 melanoma lung metastases.
• These tumor-bearing mice had first undergone total body irradiation.

The team tracked tumor burden with luciferase luminescence and monitored overall survival. Both T_C1 and T_C17 cells fought the tumor, but T_C1 cells did better: they stopped tumor growth completely, while T_C17 cells only delayed it and eventually lost control of the tumor.

IFNγ Responsiveness Determines Which Cell Type Wins

The transferred T_C1 cells made only IFNγ, not IL-17. T_C17 cells made high levels of IL-17 and, as expected for this subset, could also turn into IFNγ-producing cells. The researchers found a striking result: removing IFNγ-responsiveness from tumor cells completely flipped which T cell type worked better.

• Tumor cells needed to respond to IFNγ for T_C1 cells to fight them effectively — suggesting IFNγ-responsive genes help T_C1 cells recognize tumor cells, slow their growth, or make them more prone to apoptosis.
• Once tumor cells could no longer respond to IFNγ, T_C17 cells were able to drive complete tumor regression.
• Cytokine-neutralization tests showed IFNγ (not IL-17) was required in vivo for T_C17 cells to work.

This suggests that in T_C17 cell therapy, IFNγ needs to act on other cells in the tumor microenvironment — but IFNγ signaling inside the tumor cells themselves is, oddly, harmful to the therapy’s effect.

In the first few days after transfer, T_C1 cells multiplied faster in vivo than T_C17 cells. But by two and four weeks, T_C17 cell levels in the spleen and lungs matched or exceeded T_C1 levels — in mice with both wild-type and IFNγ-nonresponsive tumors.

This longer-term persistence may be part of why T_C17 cells produce the anti-tumor responses they do.

The two pathways work differently: IFNγ signals through the STAT1 transcription factor, while IL-17 signals through a separate ACT1 pathway that activates NF-κB. T_C17 cells also release IL-22, which activates STAT3. Crosstalk between these pathways inside tumor cells may explain why T_C1 and T_C17 cells depend so differently on IFNγ-responsiveness.

Implications for Adoptive Cell Therapy

It’s still not clear why T_C17 cells in this model could control IFNγ-nonresponsive tumors but not wild-type tumors, while T_C1 cells showed the opposite pattern. Still, these findings matter for how researchers design future adoptive cell transfer therapies.

Because T_H17 cells persist long-term in vivo and show real anti-tumor activity, some researchers have proposed them as a strong CD4⁺ partner for CD8⁺ T cells in adoptive therapy. But this study suggests effectiveness will vary across cytokine-producing T_C and T_H subsets, depending on factors like whether the tumor can respond to cytokines such as IFNγ.

Further Reading

Adoptive Transfer of Tc1 or Tc17 Cells Elicits Antitumor Immunity against Established Melanoma through Distinct Mechanisms. Yu Y, Cho HI, Wang D, Kaosaard K, Anasetti C, Celis E, Yu XZ. J Immunol. 2013 Feb 15;190(4):1873-81.

Tumor-specific Th17-polarized cells eradicate large established melanoma. Muranski P, Boni A, Antony PA, Cassard L, Irvine KR, Kaiser A, Paulos CM, Palmer DC, Touloukian CE, Ptak K, Gattinoni L, Wrzesinski C, Hinrichs CS, Kerstann KW, Feigenbaum L, Chan CC, Restifo NP. Blood. 2008 Jul 15;112(2):362-73.

Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Kryczek I, Banerjee M, Cheng P, Vatan L, Szeliga W, Wei S, Huang E, Finlayson E, Simeone D, Welling TH, Chang A, Coukos G, Liu R, Zou W. Blood. 2009 Aug 6;114(6):1141-9.

Structure and signalling in the IL-17 receptor superfamily. Sarah L. Gaffen. Nat Rev Immunol. 2009 August; 9(8): 556.

Human TH17 cells are long-lived effector memory cells. Kryczek I, Zhao E, Liu Y, Wang Y, Vatan L, Szeliga W, Moyer J, Klimczak A, Lange A, Zou W. Sci Transl Med. 2011 Oct 12;3(104):104ra100.

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