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Low pH impairs complement-dependent cytotoxicity against IgG-coated target cells.

Ezequiel Dantas1, Fernando Erra Díaz1, Pehuén Pereyra Gerber1

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Low extracellular pH significantly inhibits complement-dependent cytotoxicity (CDC) against antibody-coated cells. This finding suggests that tumor acidosis may hinder antibody-mediated tumor destruction, impacting cancer therapies.

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Area of Science:

  • Immunology
  • Biochemistry
  • Oncology

Background:

  • Local acidosis is prevalent in various diseases, including cancer.
  • The impact of extracellular pH on immune responses, particularly complement-dependent cytotoxicity (CDC), is not well understood.

Purpose of the Study:

  • To investigate the effect of low extracellular pH on complement-dependent cytotoxicity (CDC) against antibody-coated cells.
  • To determine if acidosis influences the complement system's activation pathways.

Main Methods:

  • Utilized human serum as a complement source.
  • Assessed CDC against B lymphoblast cell lines and PBMCs coated with therapeutic monoclonal antibodies (mAbs) at varying pH levels (5.5, 6.0).
  • Evaluated complement activation via alternative and lectin pathways in low pH conditions.

Main Results:

  • Extracellular pH values of 5.5 and 6.0 strongly inhibited CDC against IgG-coated cells.
  • Low pH suppressed CDC in both cell suspension and whole blood assays.
  • Acidosis prevented the activation of complement by alternative and lectin pathways.

Conclusions:

  • Severe acidosis, common in solid tumors, may impair mAb-mediated complement destruction of tumors.
  • These findings highlight a potential mechanism limiting the efficacy of antibody-based cancer therapies in acidic tumor microenvironments.